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EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure

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Clinical Practice Guidelines
EASL Clinical Practical Guidelines on the management
of acute (fulminant) liver failureq
European Association for the Study of the Liver ⇑
Summary
The term acute liver failure (ALF) is frequently applied as a generic expression to describe patients presenting with or developing an acute episode of liver dysfunction. In the context of
hepatological practice, however, ALF refers to a highly specific
and rare syndrome, characterised by an acute abnormality of liver
blood tests in an individual without underlying chronic liver disease. The disease process is associated with development of a
coagulopathy of liver aetiology, and clinically apparent altered
level of consciousness due to hepatic encephalopathy. Several
important measures are immediately necessary when the patient
presents for medical attention. These, as well as additional clinical procedures will be the subject of these clinical practice
guidelines.
Ó 2016 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.
Introduction
The term acute liver failure (ALF) is frequently applied as a
generic expression to describe patients presenting with or
developing an acute episode of liver dysfunction. It is characterised by a deterioration in liver function tests, and potentially associated with dysfunction in other organs. ALF is
frequently, but often incorrectly used to describe both acute
deterioration in liver function in patients with chronic liver
disease (a condition that should be termed acute-on-chronic
liver failure [AoCLF]), or liver involvement in systemic disease
processes. Liver injury secondary to alcohol, which presents
as alcoholic hepatitis, and other forms of AoCLF, can be difficult to distinguish from ALF on occasion. However, there
are clear differences, and different forms of management
are required.
Following extensive liver resection, patients with or without
underlying chronic liver disease, may develop a clinical
Received 7 December 2016; accepted 7 December 2016
q
Clinical practice guidelines panel: Chair: Julia Wendon; Panel members: Juan
Cordobay, Anil Dhawan, Fin Stolze Larsen, Michael Manns, Frederik Nevens, Didier
Samuel, Kenneth J. Simpson, Ilan Yaron; EASL Governing Board representative:
Mauro Bernardi
⇑ Corresponding author. Address: European Association for the Study of the Liver
(EASL), The EASL Building – The Home of European Hepatology, 7 Rue Daubin,
1203 Geneva, Switzerland. Tel.: +41 (0) 22 807 03 60; fax: +41 (0) 22 328 07 24.
y
Juan Cordoba passed away during the preparation of this chapter.
syndrome of jaundice, coagulopathy and hepatic encephalopathy (HE). The presentation is very similar to that of a posttransplant ‘‘small for size syndrome” scenario. These syndromes
are not considered within the scope of ALF, but do feature in
some ALF databases, such as the European Liver Transplant
Registry (ELTR). Extensive liver trauma is also included in ALF
databases, but is not a cause of ALF unless there is loss of both
venous and arterial inflows.
In the context of hepatological practice, ALF refers to a
highly specific and rare syndrome, characterised by an acute
abnormality of liver blood tests in an individual without underlying chronic liver disease. The disease process is associated
with development of a coagulopathy of liver aetiology, as
opposed to the coagulation disturbance seen in sepsis, and clinically apparent altered level of consciousness due to HE. The
condition of patients who develop coagulopathy, but do not
have any alteration to their level of consciousness is defined
as acute liver injury (ALI). Thus, the term ALF is appropriately
used to describe patients who develop both coagulopathy and
altered mentation and will be the subject of these clinical practice guidelines.
The features of coagulopathy, increased serum transaminases,
abnormal bilirubin and altered levels of consciousness may be
seen in patients with a variety of systemic disease processes.
Therefore, if there is no primary liver insult, these patients should
be considered to have a secondary liver injury and not ALF; management should focus on the treatment of any underlying disease
processes.
The evidence and recommendations in these guidelines have
been graded according to the Grading of Recommendations
Assessment Development and Evaluation (GRADE) system [1].
The strength of recommendations reflects the quality of the
underlying evidence. The GRADE system offers two grades of recommendation: strong (1) or weak (2) (Table 1). The CPGs thus
consider the quality of evidence: the higher the quality of evidence, the more likely a strong recommendation is warranted;
the greater the uncertainty, the more likely a weaker recommendation is warranted.
Definitions and main clinical features of ALF
The clinical course of ALF is initiated with a severe ALI. This is
characterised by a two- to threetimes elevation of transaminases
(as a marker of liver damage) associated with impaired liver function, i.e., jaundice and coagulopathy, in a patient without a
Journal of Hepatology 2017 vol. 66 j 1047–1081
Clinical Practice Guidelines
chronic liver disease. This clinical description originated from
observations of drug related hepatotoxicity, but is applicable to
all presentations [2].
ALF was originally defined by Trey and Davidson in 1970 as
fulminant liver failure, which was ‘‘a potentially reversible condition, the consequence of severe liver injury, with an onset of
encephalopathy within 8 weeks of the appearance of the first
symptoms and in the absence of pre-existing liver disease” [3].
In 1993, the syndrome was redefined to take into account the
aetiology, frequency of complications and prognosis (Table 2)
[4]. Considering jaundice as the first symptom, hyperacute liver
failure describes patients developing HE within 7 days of noting
jaundice. Acute liver failure occurs when patients develop HE
between 8 and 28 days of noting jaundice; and subacute liver
failure describes HE occurring within 5–12 weeks of jaundice
(Fig. 1). Disease duration of greater than 28 weeks before the
onset of encephalopathy is categorised as chronic liver disease.
The International Association for the Study of the Liver (IASL)
sub-committee statement (1999) defined hyperacute ALF as less
than 10 days, fulminant ALF as 10 days to 30 days and subacute
hepatic failure as 5 to 24 weeks [7].
Hyperacute presentations consist of severe coagulopathy,
markedly increased serum transaminases and initially only
moderate, if any, increase in bilirubin [8]. In contrast,
subacute/subfulminant presentations often have a milder
increase in serum transaminases, deep jaundice and mild to
moderate coagulopathy [5,9]. It should be noted, however, that
serum transaminase levels may not be considered a fully reliable
parameter for diagnosis. Patients with subacute ALF often also
have splenomegaly, ascites, and a shrinking liver volume. Once
HE develops, these patients have a very low chance of
spontaneous survival. In contrast, hyperacute presentations have
a much greater chance of spontaneous recovery, despite having
significant extrahepatic organ failure [10].
The disturbances to coagulation required to define ALF are
determined by a prolongation of International Normalised
Ratio (INR), usually >1.5, or a prolongation of prothrombin
time (PT) [11]. Although this remains, at present, the
accepted definition, it could be argued that a greater prolongation of INR should be required to define ALF. However, the
Table 1. Grading evidence and recommendations (adapted from GRADE
system).
Grade
I
II-1
II-2
II-3
III
Grade
1
2
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of evidence
Randomized, controlled trials
Controlled trials without randomization
Cohort or case-control analytical studies
Multiple time series, dramatic uncontrolled experiments
Opinion of respected authorities, descriptive epidemiology
of recommendation
Strong recommendation: Factors influencing the strength of the
recommendation included the quality of the evidence, presumed
patient-important outcomes, and cost
Weaker recommendation: Variability in preferences and values, or
more uncertainty: more likely a weak recommendation is
warranted. Recommendation is made with less certainty: higher
cost or resource consumption
INR is not standardised, and was designed to monitor warfarin therapy [12]. As a more accurate marker many clinicians would now suggest prolongation of PT in the context
of the normal range for a particular laboratory. The other
defining features of ALF, i.e., jaundice and HE, are required
to be clinically manifested. However, in very young children
and neonates, ALF may occur in the absence of HE, albeit
with a definition that requires a much greater degree of
coagulopathy (INR >4) [10]. Initial mental alterations may
be subtle and therefore should be actively sought. Efforts
have been made to develop more sensitive measures to
define early grades of HE, but they are not available in routine clinical settings and certainly not in district hospitals
where most patients first present for medical attention [13].
The concept of minimal HE is well recognised in patients
with cirrhosis, but is poorly characterised in patients with
ALF. Characterisation of minimal HE may be a useful tool
in clarifying management plans for those with subacute presentations, although less relevant to hyperacute and acute
ALF presentations. In subacute liver failure, the presence of
HE usually occurs late in the disease course and is often a
manifestation of infection; once HE develops the patient has
a very short window to obtain a liver transplant, if any.
Recent proposals suggest that in an appropriate clinical context accompanied by a shrinking liver volume, super urgent
listing could be undertaken in this cohort, without the presence of clinically clear encephalopathy. Even with a definition
set there are clear differences between acute and hyperacute
liver failure (which have similar phenotype and clinical
course), and subacute liver failure (which presents with a different clinical course). Separation of these two groups should
be considered in future guidance, regarding prognosis and
clinical management pathways.
Another prerequisite for defining cases of ALF is the absence
of previous severe fibrotic or cirrhotic chronic liver disease.
Specific exceptions are the acute de novo presentation of
autoimmune hepatitis and Budd-Chiari syndrome. In these conditions, an underlying chronic disease will not have been
recognised or diagnosed previously, and there should be no
clinical or histological evidence of cirrhosis. Wilson disease is
another exception category; a clinical scenario when there is
a clear chronic liver disease with splenomegaly, albeit frequently undiagnosed. The precipitant event is often a viral
infection, [14] or in adolescents, non-compliance with therapy.
Nevertheless, these patients are considered as having ALF since
they share the poor prognosis, a common clinical picture of
acute failure of the liver, and present with significant coagulopathy and encephalopathy.
A small group of patients whom frequently cause consternation are those without overt fibrosis but with evidence of a liver
pathology (e.g., metabolic syndrome and fatty liver, hepatitis C or
B), who then develop an ALI. These patients may progress to
encephalopathy, severe coagulopathy, and elevated serum
transaminases. In the context of a clinical scenario, supported
by ultrasound and axial imaging of no overt fibrosis or portal
hypertension these patients would normally be categorised as
ALF.
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Table 2. The clinical course of different ALF aetiologies.
Precipitant
Examples
Presentation
Viral
Drugs/toxins
Hepatitis A, E, B (less frequent CMV, HSV, VZV, Dengue)
Paracetamol (acetaminophen), phosphorous, Amanita phalloides
Anti-tuberculous, chemotherapy, statins, NSAI, phenytoin, carbamazepine, ecstasy,
flucloxacillin
Budd Chiari
Hypoxic hepatitis
Pre-eclamptic liver rupture, HELLP, fatty liver of pregnancy
Wilson disease, autoimmune, lymphoma, malignancy, HLH
Acute/fulminant
Acute/fulminant and subacute/subfulminant
Acute/fulminant
Vascular
Pregnancy
Other
Acute/fulminant and subacute/subfulminant
Acute/fulminant
Acute/fulminant
Acute/fulminant and subacute/subfulminant
CMV, cytomegalovirus; HSV, Herpes simplex; NSAI, non-steroidal anti-inflammatory; HELLP, haemolysis, elevated liver enzymes, low platelets; HLH, haemophagocytic
lymphohistiocytosis.
Recommendations
Severe acute liver injury defines a syndrome characterised
by markers of liver damage (elevated serum transaminases) and impaired liver function (jaundice and INR
>1.5) which usually precedes clinical encephalopathy (evidence level II-2, grade of recommendation 1).
Patients with an acute presentation of chronic autoimmune hepatitis, Wilson disease and Budd-Chiari syndrome
are considered as having ALF if they develop hepatic
encephalopathy, despite the presence of a pre-existing
liver disease in the context of appropriate abnormalities
in liver blood tests and coagulation profile (evidence level
II-2, grade of recommendation 1).
The clinical appearance of hepatic encephalopathy is crucial for the diagnosis of ALF but mental alterations may
be initially subtle and intensive screening at the first sign
of hepatic encephalopathy is mandatory (evidence level
II-2, grade of recommendation 1).
Considerations for future studies
Biomarkers to help predict the progression from ALI to
ALF.
Development and dissemination of better tests for subtle
hepatic encephalopathy in patients with subacute
presentations.
Review of INR/prothrombin cut-off for definition of ALF in
the context of both hyperacute, acute and subacute liver
failure.
Burden of ALF within Europe
The burden of ALF within the European Union (EU) remains
unclear, with no collection of data regarding prevalence or
incidence. Estimates are based on data presented in clinical
series from referral and transplant units. Analysis of liver
transplantation (LTx) data in the ELTR demonstrates that only
8% of all transplants are performed because of ALF as the primary
indication. Sub-analysis of this 8% shows that 19% of cases are
related to viral infection, 18% to drug-induced liver injury, 4%
secondary to toxic insults and 3% postoperative or traumatic
events, whilst 56% are attributable to unknown or other causes
[15].
LTx is utilised in a minor proportion of patients with ALF; only
18.2% of patients received LTx according to the Kings College
‘‘Look-Back” [8]. However, the utilisation of LTx varies between
countries, within different transplant units in a single country
and between different aetiologies (Table 3). The incidence of
virally induced disease has declined substantially in Europe.
However, worldwide (especially Asia and Africa), it remains the
commonest cause of ALF, with hepatitis A, E and B being the
predominant causative viruses. The most frequent aetiology of
ALF in Europe is now drug-induced liver injury (DILI); in some
areas, this is predominantly from paracetamol (acetaminophen)
overdose (POD), whilst in others non-paracetamol-induced drug
toxicity prevails [10,27,28]. Estimated incidence of ALF in
Scotland, which has a single national centre for referral, was
0.62/105/year. POD was the single most common cause, with an
incidence of 0.43/105/year. Adding further complexity in estimating the true burden of ALF within the EU is the report from the
same region that suggests less than 50% of cases that die following
POD are transferred to this national referral centre [29]. What is
clear is that ALF is a rare clinical condition but the true incidence
across the EU is unknown, and disease burden is not clearly
defined.
Recommendations
ALF is a rare diagnosis and multicentre data, such as the
European Acute Liver Failure Registry, is required to assess
outcome, optimal management and conduct appropriate
multicentre studies (evidence level II-2, grade of recommendation 1).
Whilst hyperacute and acute syndromes are usually easily
diagnosed, subacute ALF may be mistaken for cirrhosis and
the opportunity to be considered for transplantation lost
(evidence level II-2, grade of recommendation 1).
Clinical utilisation of transplantation varies upon aetiology
and region (evidence level II-3, grade of recommendation 2).
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Clinical Practice Guidelines
Jaundice to encephalopathy interval (weeks)
0
1
2
4
8
12
//
(a) O’Grady et al. [4]
‘Hyper acute’
‘Acute’
‘Sub acute’
(b) Bernuau et al. [5]
‘Fulminant’
‘Sub fulminant’
(c) Japanese consensus [6]
‘Fulminant’
Sub-class: ‘Acute’
‘Late-onset’
‘Sub acute’
Fig. 1. A summary of sub-classifications of ALF.
Recommendations
Considerations for future studies
Enrolment of all patients with ALF into a common webbased database with internationally agreed definitions of
ALF and sub-classification.
Internationally accepted assessment of coagulation abnormalities in ALF.
Development of EU wide epidemiological studies to define
ALF and ALI prevalence and incidence.
Assessment and management at presentation
Several important measures are immediately necessary when the
patient presents for medical attention (Table 4). Early discussion
with a tertiary liver centre should be undertaken, even if the
patient is not yet considered for transfer.
Rule out the presence of cirrhosis and/or alcoholic-induced liver
injury
The clinical picture and radiology of patients with ALF, especially in the case of subacute ALF, can mimic cirrhosis. The
loss of hepatic mass and regenerative nodules induce irregular
contours of the liver. This, along with the presence of ascites
and mild splenomegaly, are often signs radiologists use to
diagnose the presence of cirrhosis. Access to medical history
is therefore crucial. Liver biopsy, preferably by the transjugular route, can be useful to exclude cirrhosis, malignancy or
alcohol-induced ALI. Liver biopsy has also been undertaken
by mini laparoscopy without bleeding risk, but the risk of
general anaesthesia and encephalopathy must be considered
[30]. Liver biopsy is not helpful, however, for a prognosis
based on the degree of liver necrosis, due to the problem of
sample error [31].
1050
The clinical picture and the radiology of subacute liver failure can mimic cirrhosis (evidence level II-3, grade of recommendation 1).
The indications for liver biopsy in ALF are limited, and
should be performed preferably by a transjugular route,
in a centre experienced in its use, and with access to a
histopathologist with liver experience. Incidence of underlying chronic liver disease, malignancies or alcoholinduced liver disease should be excluded if possible, but
this does not provide prognostic information (evidence
level II-3, grade of recommendation 1).
Early referral of patients to a specialist centre will allow
appropriate delineation of those likely to benefit from
transplantation and offers an environment where focused
expertise provides the greatest chance of spontaneous survival without LTx (evidence level III, grade of recommendation 1).
The search for an aetiology
The aetiology of ALF is an important indicator for prognosis and
the treatment strategy, especially in the necessity for emergency
LTx (Table 5). Clinical features may be typical in certain causes of
ALF (Table 6).
Aetiologies with no indication for emergency LTx
Malignant infiltration of the liver. Extensive malignant infiltration
of the liver, which can occur in metastatic breast cancer and lymphoma, can result in ALI or ALF. It is important to make this diagnosis early, since these patients are not candidates for LTx. In
patients with a history of cancer or hepatomegaly, malignant
infiltration should be ruled out with imaging and/or liver biopsy.
Liver imaging requires experienced review, frequently has a pattern of diffuse infiltration as opposed to multiple deposits, and
can be difficult to define as a likely malignant infiltrative picture
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Table 3. Epidemiological studies of ALF in different countries.
Country
UK*
US
Canada
Scandinavia France
Spain
Chiley
Australasia Sudan
India
Germany
Reference
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et al. [16]
310
1994–
2004
43
8
Ostapowicz
et al. [17]
308
1998–
2001
39
13
Tessier
et al. [18]
81
1991–
1999
15
12
Brandsaeter
et al. [19]
315
1990–
2001
17
10
Ichai
et al. [20]
363
1986–
2006
7
21
Escorsell
et al. [21]
267
1992–
2000
2
14
Uribe
et al. [22]
27
1995–
2003
0
7
Gow et al.
[23]
80
1988–
2001
36
6
Mudawi
et al. [24]
37
2003–
2004
0
8
Khuroo
et al. [25]
180
1989–
1996
0
0.6
Hadem
et al. [26]
109
2008–
2009
9
32
7
12
30
12
33
37
37
14
27
21
30
13
17
19
27
16
43
17
18
21
32
15
44
11
34
10
38
27
68 (44
Hep E)
31
0
No. of cases
Years
Paracetamol (%)
Non-paracetamol
drug reactions (%)
Hepatotropic
viruses (%)
Indeterminate (%)
Other causes (%)
*
y
24
14
Patients listed for orthotopic liver transplantation only.
Paediatric patients only.
outside a specialist centre. The liver biochemistry classically
shows an elevated alkaline phosphatase and gamma-glutamyl
transferase but on occasions may present with marked increase
in serum transaminases, caused by hepatocyte ischaemia resultant upon the infiltration. In patients with lymphoma, a greater
elevation of lactate dehydrogenase is observed compared to
serum transaminases [32,33]. Consideration of an underlying
malignant process and potential infiltration should also be considered in acute presentations of Budd-Chiari syndrome [34].
Acute ischaemic injury. Acute ischaemic injury of the liver is especially common in elderly patients. The risk of this condition is
increased in patients with cardiovascular disorders and severe
congestive heart disease. Ischaemic injury often occurs in the
presence of right heart dysfunction and associated liver congestion, with a subsequent episode of hypoxia or hypotension (so
called hypoxic hepatitis). However, the absence of a documented
episode of hypotension or hypoxia does not exclude this condition. Hypoxic hepatitis has a prevalence of between 1.2 and
11% in intensive care series. Three aetiological subgroups may
be distinguished by respiratory failure, cardiac failure and septic
shock/hypotension [35].
Hypoxic hepatitis is a secondary form of ALF. Therefore, the
primary presenting organ failure needs to be addressed and
managed to facilitate liver recovery [36], and LTx should not
normally be considered. A characteristic pattern of liver blood
tests are seen, which are similar to those observed in
N-nitrosodimethylamine (NDMA) and paracetamol overdose.
Aspartate transaminase (AST) are often >10,000 IU/L and at least
twice the value of alanine aminotransferase (ALT), and frequently,
bilirubin levels are normal at initial presentation. Marked elevation of transaminases and severe coagulopathy are seen, as with
other causes of hyperacute ALF such as paracetamol and ecstasy
(3,4-Methylenedioxymethamphetamine
[MDMA])
overdose
[37–39]. HE and hyperammonaemia are also not infrequent.
Liver ischaemia is also seen following trauma and surgical
mishap when there is loss of vascular inflow into the liver. In
these cases, LTx should be not considered unless there is loss of
all vascular inflows.
Other systemic diseases. Other conditions may also result in ALF but
are not an indication for LTx. Haemophagocytic lymphohistiocytosis (HLH) may be precipitated by viral or fungal infections or occur
in the context of haematological malignancy [40]. Similarly, infectious disease processes such as malaria, dengue and rickettsiosis
may result in secondary liver failure [41]. ALF may also be seen
in the context of systemic mitochondrial failure following some
toxic ingestions (yellow phosphorous) or related to some drug
related toxicities. The role of LTx in the latter setting is not clear.
Recommendations
In patients with a history of cancer or significant hepatomegaly, malignant infiltration should be excluded by
imaging or liver biopsy (evidence level II-3, grade of recommendation 1).
Acute ischaemic injury will resolve after improvement of
haemodynamic status, and is not an indication for emergency LTx. It can occur in the absence of a proven period
of hypotension (evidence level II-3, grade of recommendation 1).
Table 4. Immediate measures at presentation of patients with ALF to medical care.
In patients with severe ALI, screen intensively for any signs of hepatic encephalopathy.
Exclude the presence of cirrhosis, alcohol induced liver injury or malignant infiltration of the liver.
Consider whether the patient does not have contraindications for emergency LTx: the finding of contraindications should not preclude transfer
to a tertiary unit.
Searching for an aetiology allows treatment to be instituted and facilitates prognostic stratification.
Transfer to a specialised unit early if the patient has an INR >1.5 and onset of hepatic encephalopathy or other poor prognostic features.
Early discussion with a transplant unit even if the patient does not need transfer at that time point.
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Clinical Practice Guidelines
Table 5. Primary or secondary causes of ALF and need for transplantation.
Disease group
Hepatic/primary ALF
(Emergency transplantation may be a treatment option)
Extrahepatic/secondary liver failure and AoCLF
(Emergency transplantation is not a treatment option)
Acute liver failure
Drug related
Acute viral hepatitis
Toxin-induced ALF
Budd-Chiari syndrome
Autoimmune
Pregnancy related
Ischaemic hepatitis (HH)
Systemic diseases:
Haemophagocytic syndromes
Metabolic disease
Infiltrative disease
Lymphoma
Infections (e.g., malaria)
Chronic liver disease presenting
with a phenotype of ALF
Fulminant presentation of Wilson disease
Liver resection for either secondary deposits or primary
liver cancer
Alcoholic hepatitis
Autoimmune liver disease
Budd-Chiari
HBV reactivation
Aetiologies which form a possible indication for emergency LTx
Drug-induced hepatotoxicity
Paracetamol overdose. Paracetamol intoxication can be a single
time point POD with intentional suicide or para-suicidal motivation, a situation especially seen in the UK. Alternatively, accidental hepatotoxicity can occur in patients taking excessive amounts
of paracetamol to relieve pain, which is often associated with
ingestion over several days (staggered presentation). Accidental
POD can be associated with alcohol dependence, ingestion of
multiple paracetamol containing compounds or the use of
opioid-paracetamol compounds [8,42–44]. Increased sensitivity
to paracetamol is seen in those with decreased glutathione
reserves, e.g., fasting, excessive alcohol consumption and in those
taking certain regular medications, such as phenytoin [45].
Toxicology screening and determination of the circulating
paracetamol level needs to be done at admission in every patient,
especially in cases with hyperacute ALF and significantly elevated
serum transaminases. However, even though paracetamol metabolism is reduced with liver failure, paracetamol is usually undetectable at the time of presentation, and aetiology often has to be
based on clinical presentation, history and typical laboratory
results.
POD-induced hepatotoxicity is characterised by extreme elevations of serum aminotransferase (usually >10,000 IU/L) and
normal bilirubin levels. Metabolic acidosis, elevated serum lactate, hypoglycaemia and acute kidney injury (AKI) can occur in
early stages of clinical evolution. Accidental staggered POD
produces smaller elevations of serum aminotransferase, but more
marked organ failure at presentation is frequently observed. This
cohort is less easy to stratify regarding prognosis, as their INR or
PT are less elevated. Other scoring systems, such as sequential
organ failure assessment (SOFA) score, may be preferred
[16,27,46].
Very early presentation of patients with significantly elevated
paracetamol levels can be associated with marked metabolic acidosis and elevated lactate, but only mild elevation of transaminase levels and minimal, if any, coagulopathy. This is a separate
entity to the later ALF that may develop. This clinical syndrome
is considered as a direct drug effect, relating to functional mitochondrial standstill, and resolving with falling paracetamol
levels. These patients should be treated with appropriate fluid
resuscitation, N-acetylcysteine (NAC), and may need renal
replacement therapy (RRT) to treat the acidosis. In these cases,
other compounding aetiologies should also be sought such as salicylate, tricyclic or methanol ingestion.
The clinical evolution of POD is often that of rapidly progressive multi-organ failure (MOF) and HE, which may progress from
a mild grade 1 to grade 4 coma over a period of hours. Patients
who do not meet criteria for emergency LTx have a good prognosis, and those who meet the criteria may still have a survival rate
of 20–40% with modern intensive care management, according to
recent reports. Significantly improved outcomes with medical
management have been reported, and are achieved despite poor
prognostic criteria [16,46]. The clinical presentation and evolution
is different between hepatotoxicity induced by POD and most
Table 6. Differential diagnosis of ALF based on clinical features.
Aetiology
Clinical features
Malignant infiltration
Acute ischemic injury
History of cancer, massive hepatomegaly; elevated alkaline phosphatase or other tumour markers.
Marked elevation of aminotransferases, increased lactic dehydrogenase and creatinine, which normalise soon after stabilisation
of haemodynamic instability. Patients with severe congestive heart disease or respiratory disease.
Very high levels of aminotransferases and low level of bilirubin. Rapidly progressive disease, acidosis and renal impairment.
Low phosphate may be seen as a good prognostic marker but replacement is required.
Subacute clinical course can mimic cirrhosis, clinically and radiographically.
Paracetamol
Non-paracetamol drug
toxicity
Acute Budd-Chiari
syndrome
Wilson disease
Mushroom poisoning
Autoimmune
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Abdominal pain, ascites and hepatomegaly; loss of hepatic venous signal and reverse flow in portal vein on ultrasound.
Young patient with Coombs (DAT) negative haemolytic anaemia with a high bilirubin to alkaline phosphatase ratio; KayserFleischer ring; low serum uric acid level; markedly increased urinary copper.
Severe gastro-intestinal symptoms after ingestion; development of early AKI.
Usually subacute presentation – may have positive autoantibodies, elevated globulin and characteristic lymphocyte pattern
when compared to viral and seronegative aetiologies.
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other drugs causing ALF. NAC is associated with improved outcome in patients presenting with POD [47–49]. Other drug toxicities are usually associated with a less significant elevation of
serum aminotransferases, higher bilirubin levels and less associated extrahepatic organ dysfunction than are observed in patients
with POD. Often a mixed or cholestatic pattern of liver function
abnormalities are observed. The mode of cell death is different
depending on aetiology, and different therapeutic interventions
may be required to promote regeneration and repair [50–52].
Non-paracetamol. Less than 10% of patients with nonparacetamol DILI progress to ALF but if they do, up to 80% die or
require emergency LTx [2]. Drug-induced ALF arises more often
in older patients, especially above 60 years [53–56]. A hepatocellular DILI normally presents with an acute ALF clinical course,
compared with cholestatic DILI, which is more likely to lead to a
subacute course. A hypersensitivity reaction is uncommon and
seen in less than one third of patients [57–59]. In contrast with
most DILI, ecstasy-induced liver injury is a hyperacute presentation resulting from or associated with severe hyperthermia with
multiple organ involvement, profound coagulopathy and severe
rhabdomyolysis. This clinical picture is identical to other forms
of heat shock related liver injury [37,38]. Assessment of prognosis
in the first few day can prove more challenging in multi-organ
compared to primary hepatic failure. LTx is rarely (if ever)
required, despite profound abnormalities in blood tests and physiology. In the majority of cases LTx will not alter the outcome.
Drug reaction with eosinophilia and systemic symptoms (DRESS)
syndrome is a very rare presentation and should always be considered in those with fever, eosinophilia, marked cutaneous rash
and lymphadenopathy. Sulphur containing compounds, some
anticonvulsants and antimicrobials are more often associated
with DRESS. High dose steroid therapy should be considered prior
to the development of ALF in patients with DRESS [60]. Concurrent
viral infections should always be sought in those with DILI, as they
are frequent and have been associated as trigger factors for DILI.
The classes of drugs most frequently associated with ALF are
antituberculosis drugs (especially isoniazid [61]), antibiotics
(especially nitrofurantoin and ketoconazole), anti-epileptics
(especially phenytoin and valproate), non-steroidal antiinflammatory drugs, and a wide group of other medication such
as propylthiouracil and disulfiram [56,62]. Guidelines have been
issued by various thoracic societies for the management and
withdrawal of anti-tuberculous chemotherapy in patients who
develop hypertransaminasaemia or jaundice [63].
Some patients will not automatically report the ingestion of
drugs, especially in the context of illicit drugs, herbal medicine
products or nutritional supplements. The latter is especially
prevalent in East Asia [62]. Intensive questioning of the patient
and their relatives is necessary at different opportunities and
by several physicians to comprehensively exclude a drug cause
for ALF. DILI may only become symptomatic several weeks after
ingestion. A record of all drugs (prescribed and non-prescribed),
vitamin supplements and herbal medicines taken within the last
6 months should be collected. Other causes of severe ALI should
always be ruled out, since DILI is often a diagnosis of exclusion.
This especially applies to autochthonous hepatitis E virus (HEV)
infection, which may be misdiagnosed as DILI and occurs more
frequently in similar demographic groups. In rare cases, drugs
such as long-acting niacin, cocaine or methamphetamine, can
induce liver ischaemia via hypoperfusion. Acute ischaemic injury
caused by these agents is characterised by a marked elevation of
both aminotransferases and lactic dehydrogenase, a rapidly
progressive prolongation of the PT, and increased serum creatinine. These abnormalities normalise soon after hemodynamic
stabilisation [64]. As with all aetiologies of hypoxic hepatitis,
the majority of cases survive with medical management alone.
Viral hepatitis. The following hepatic viruses can cause ALF: hepatitis B virus (HBV), hepatitis A virus (HAV) and HEV.
HBV. HBV is the most common viral cause of severe ALI and
ALF, due to either de novo infection, delta superinfection or reactivation in a patient with previous HBV infection [65,66]. Vaccination has led to a significant drop in the incidence of HBV
cases, with a concomitant fall in HBV induced ALF [67,68]. Fewer
than 4% of cases with acute hepatitis B will develop ALF, but mortality is higher than in HAV or HEV infections [25,68–70]. Early
treatment with antiviral therapy decreases the risk of progression
to ALF [71]. Reactivation in chronic carriers occurs during or after
treatment-induced immunosuppression for solid organ or
haematological malignant disease and has a higher mortality
than de novo infections [72,73]. Increasingly, reactivation may
be seen in those patients treated with rituximab, either in the
context of chemotherapy or treatment of immune mediated diseases [74,75]. Screening of populations is essential prior to significant immunosuppression or administration of antiviral
prophylactic treatment in patients with previous HBV exposure.
HBV related ALF presents with an acute phenotype. As observed
with other hepatitis viruses and causes of ALF, the prognosis of
HBV-induced ALF is worse in the elderly and in those with severe
co-morbidities [76].
HAV. Less than 1% of patients with acute HAV will develop
ALF, and several cofactors will affect its evolution [77]. Usually,
hepatitis A has a hyperacute or acute clinical course. ALF due to
HAV is also more common in older patients, and in this patient
group has a worse prognosis [78,79].
HEV. Acute hepatitis due to HEV is most frequently seen in
patients who recently travelled to endemic areas. However, sporadic cases of acute HEV are detected in Europe [80,81]. Hepatitis
E results in a hyperacute pattern of ALF and although mortality is
low, worse outcomes are observed in elderly patients, those with
pre-existing but undiagnosed chronic liver disease and pregnant
women [82–84]. The disease presentation in Asia and Africa is
more severe than that seen in Europe [85].
Other viral infection. Herpes simplex virus types 1 and 2 and
varicella zoster are other rare viral causes of ALF. Even though
these infections are more commonly seen in immunosuppressed
patients, they may also occur in immunocompetent individuals.
The absence of skin lesions does not exclude the diagnosis.
Screening of blood for cytomegalovirus (CMV) and Epstein–Barr
virus (EBV) using nucleic acid testing should be undertaken in
all patients where the aetiology of ALF is not clear [86,87]. The
development of DILI can also be potentiated by the activation
of the herpes and CMV viruses, along with host drug interactions
[88]. The presence of these viral infections may not always represent the aetiology of the ALF but may be a co-factor and consideration for treatment. In the context of immunosuppression, such
viral infections may also be of importance as a primary aetiology.
Autoimmune hepatitis. The presence of other autoimmune disorders in a patient presenting with ALF should raise suspicion of
autoimmune hepatitis as the aetiology. These patients often have
an elevated globulin fraction and positive autoantibodies, but
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these may also be absent in a proportion of cases [89–92]. Equally
however, mildly positive autoantibodies may be seen in a variety
of aetiologies, and it should not be assumed that autoimmune
disease is the primary driver of the liver injury. Liver biopsy
may be required to determine the diagnosis. Treatment with steroids may be effective if given early. In the context of ALF, however, steroids are often ineffective and potentially deleterious,
as they may favour septic complications [93]. Thus, a lack of
improvement within seven days should lead to listing for emergency liver transplant (LT) without delay.
Indeterminate aetiology. In some patients, usually presenting with
an acute or subacute ALF phenotype, no aetiology can be identified
[10]. A proportion of these patients may have taken drugs or xenobiotics, which they do not not (or cannot) recall. Others provide a
history compatible with a viral phenotype, although no specific
viral aetiological agent can be identified [89]. Some subsequently
present with immune mediated features, suggesting that the original disease may have had an autoimmune aetiology. In some of
these groups, as well as in those of a known aetiology, the potential
for paracetamol induced co-toxicity may be raised by the presence
of paracetamol adducts [42,94]. Equally, studies have suggested
that some cases of presumed seronegative aetiologies may have
a hepatitis E infection, and appropriate tests regarding sensitivity
and specificity should always be undertaken [70].
Considerations for future studies
Further continuous update of the European Acute Liver
Failure Registry.
Review of criteria defining poor prognosis in the context of
modern critical care and support.
Application of biomarkers to further delineate cofactors in
the development of ALF (e.g., paracetamol adducts, viral
nucleic acid testing).
More uncommon aetiologies of ALF. In this group of aetiologies, a
specific treatment or intervention can be started. However, in
the majority of the cases, the positive effect of the treatment will
often be too late to be beneficial. Therefore, if these patients fulfil
criteria for LTx, consideration for emergency surgery should not
be delayed.
Budd-Chiari syndrome. An acute Budd-Chiari syndrome is characterised by abdominal pain, ascites and hepatomegaly. Diagnosis is made based on imaging of the liver. Testing for
hypercoagulable conditions and screening for underlying malignancies are necessary [34,95].
Recommendations
Drug-induced liver injury, especially paracetamol toxicity,
is the most frequent cause of severe ALI and ALF. At admission, a toxicology screen and determination of paracetamol level are necessary in every patient, although levels
will frequently be negative. If the patient already has coagulopathy and increased serum transaminases, N-acetyl
cysteine therapy should be given (evidence level II-2,
grade of recommendation 1).
Prognosis is worse in patients with staggered ingestion of
paracetamol. These cases are more likely to develop multiple organ failure when compared to those with single
ingestion point (evidence level II-3, grade of recommendation 1).
ALF caused by non-paracetamol drug-induced hepatotoxicity, is a diagnosis of exclusion (evidence level III, grade
of recommendation 2).
Screening for viral aetiologies and co-factor effects should
always be undertaken (evidence level II-2, grade of recommendation 1).
Autoimmune aetiology should be suspected in patients
presenting other autoimmune disorders, elevated globulin
fraction and autoantibodies. These features, however, may
be absent and liver biopsy may be required. Early treatment with steroids may be effective; however, lack of an
improvement within seven days should lead to listing for
emergency LTx without any delay, as steroids may
increase mortality because of septic complications (evidence level II-2, grade of recommendation 1).
1054
Wilson disease. The classic presentation of acute Wilson disease includes HE in young patients (<20 years) with a Coombs
negative haemolytic anaemia, and high bilirubin to alkaline phosphatase ratio. In 50% of cases, Kayser-Fleischer rings are present.
There is often renal dysfunction and serum uric acid level is low.
Serum caeruloplasmin can be very low but may be normal or
increased in the acute situation [96,97]. Serum caeruloplasmin
is also reduced in 50% of other aetiologies of ALF. Serum and urinary copper are markedly increased [98,99]. There may be a concurrent viral precipitant or non-compliance with medication in a
previously diagnosed case of Wilson disease. Prognosis is welldefined with specific prognostic modelling [100].
Mushroom poisoning. Mushroom poisoning, usually by amanita
phalloides (the most toxic of the mushroom species regarding
hepatotoxicity), can cause ALF [101,102]. Although it occurs very
rarely, recent mushroom ingestion should always be sought in a
patient with ALI or ALF. There is no routine laboratory test to
identify the toxins. Severe gastrointestinal symptoms with profuse vomiting and diarrhoea within hours or a day after ingestion
is suggestive for mushroom poisoning. The development of acute
renal failure, secondary to volume depletion, normally precedes
the development of liver failure. Prognosis should be judged in
a similar way to the models for other hyperacute syndromes,
such as paracetamol.
Pregnancy related ALF. There are two hepatic emergencies
which occur in the third trimester of pregnancy: haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and
acute fatty liver of pregnancy (AFLP). HELLP should be differentiated from atypical haemolytic uraemic syndrome and thrombotic
thrombocytopenic purpura [103]. AFLP is characterised by extensive hepatic steatosis and usually presents with abdominal pain
and malaise. Transaminases are relatively low. Hypoglycaemia
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is common, and elevated urate levels are also seen as maybe
polyuria and polydipsia. Other organ failures occur, including
pancreatitis [87,103,104]. Maternal mortality is around 20%.
Prompt delivery of the baby in both these emergency scenarios
offers a good outcome, and emergency LTx is rarely needed.
Persistent elevation of lactate levels in the presence of severe
HE potentially best identifies patients at greatest risk of death
or LTx.
When liver failure occurs specifically in pregnancy, consideration should also be given to liver rupture associated with preeclampsia. This normally presents as sudden onset of right upper
quadrant pain and requires distinction from pulmonary embolus.
Management is normally conservative but may require
laparotomy and packing if rupture through the capsule causes
significant bleeding. Extensive subcapsular haematoma may
result in ischaemic compression of liver parenchyma and rarely
compression of the hepatic veins, resulting in a syndrome similar
to Budd-Chiari [105].
ALF induced by hemi-hepatectomy. Extensive loss of liver parenchyma after resection of the liver can provoke ALI. Most
patients will recovery spontaneously if resection is performed
in the absence of an advanced liver disease. It is not an accepted
indication for emergency LTx. However, emergency LTx has been
reported in cases of ALF induced by living donor liver graft failure
[106].
Hyperthermic injury from heat shock. This may be seen in association with recreational drug use, such as ecstasy, but may also
be seen in those undertaking physical exertion in high ambient
temperatures and following prolonged fitting, again usually in
high ambient temperatures [107].
Secondary aetiologies of ALF/ALI. In any patient presenting with
increased serum transaminases and/or cholestasis and coagulopathy, where the aetiology is not primarily hepatic in aetiology,
screening for other factors should be undertaken. This should
include sepsis [108], malaria, leptospirosis, rickettsial diseases,
thyroid disease [40,109], Stills disease, and haemophagocytic
syndromes [39,110]. The latter two lead to markedly elevated ferritin levels and elevated triglyceride levels in the latter. In Asia
and Africa, ALF may be seen in conjunction with systemic
multiple organ involvement following yellow phosphorous
poisoning, a syndrome resulting in mitochondrial toxicity.
These conditions are not commonly accepted indications for
emergency LTx.
Recommendations
Assessment of the clinical context is crucial to identify less
common causes of ALF (evidence level III, grade of recommendation 1).
ALF presenting with gross ascites should lead to suspicion
of acute Budd-Chiari syndrome. Diagnosis of this condition
is based on imaging techniques (evidence level II-3, grade
of recommendation 1).
Coombs negative haemolytic anaemia and high bilirubin
to alkaline phosphatase ratio are features of ALF due to
Wilson disease (evidence level II-3, grade of recommendation 1).
In cases of HELLP and AFLP, the treatment of choice is
prompt delivery of the baby, especially in case of elevated
lactate levels and hepatic encephalopathy. Screening for
putative fatty acid defects should be offered (evidence
level II-3, grade of recommendation 1).
Screening for systemic diseases presenting as ALF should
be undertaken (evidence level III, grade of recommendation 1).
General support management outside ICU
Clinical assessment
A comprehensive clinical assessment and history taking of
patients and their relatives at admission is of upmost importance with specific questions for aetiology, comorbid conditions,
to exclude conditions which form no indication for emergency
LTx. This should also help to define the interval between
jaundice and the first signs of HE to classify the subtype of
ALF (Table 7).
Table 7. Anamnesis of patient and relatives at admission.
Search for an aetiology:
Use of medication (ask specifically for paracetamol and paracetamol containing compounds), herbal medicine and food supplements <6 month
Pregnancy
History of a chronic liver disease
Substance abuse
History of suicidal attempt/depression
Gastrointestinal complaints after mushroom ingestion
Conditions permissive for ALF:
Travelling in viral hepatitis endemic areas (HBV, HEV)
In receipt of immunosuppressive or chemotherapy
History of autoimmune disease
Conditions that may impact upon decision in respect to emergency LTx:
Active and dependent alcohol or substance misuse (individualised decision making)
History of cancer in recent past (specialist input required)
Severe congestive heart disease or respiratory co-morbidity
Interval between onset of jaundice and first signs of hepatic encephalopathy
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Table 8. Laboratory analyses at admission.
For assessing the severity of the disease:
PT, INR or factor V and full coagulation screen including fibrinogen
Liver blood tests including LDH and conjugated and unconjugated
bilirubin and creatinine kinase
Assessment of renal function:
urine output: hourly.
low urea is a marker of severe liver dysfunction.
creatinine may be difficult to assay in the context of
elevated bilirubin.
Arterial blood gas and lactate
Arterial ammonia
For aetiology:
Toxicology screen in urine and paracetamol serum level
Serological screen for virus infections
HBsAg, anti-HBc IgM (HBV DNA), delta if positive for HBV
anti HAV IgM
anti-HEV IgM
anti-HSV IgM, anti VZV IgM, CMV, HSV, EBV, parvovirus
and VZV PCR
Autoimmune markers: ANA, ASMA, anti-soluble liver antigen,
globulin profile, ANCA, HLA typing
For testing for complications:
Lipase or amylase
Laboratory investigation
At admission, specific laboratory analyses are needed to assess
the severity of the liver injury, to diagnose the aetiology, to define
prognosis for patients who are candidates for emergency LTx, and
to rule out complications such as acute pancreatitis (Table 8).
Arterial blood gas may be considered alongside a baseline
arterial ammonia measurement. Blood urea will frequently be
pathologically low and is not a reflection of renal function, which
is best assessed by urine output and creatinine.
Diagnostic procedures, monitoring and standard care at admission
Chest radiography, baseline echocardiography (ECG), and liver
echography (interrogating patency and direction of flow in vessels in addition to liver texture and size, splenic size) should be
obtained. Axial computed tomography (CT) imaging should be
considered to examine liver texture and volume, vascular integrity, exclude pancreatitis and presence of umbilical vein patency
(cirrhosis) (Table 9).
At present, the most frequent causes of death in patients with
ALF are MOF and severe sepsis. Therefore, the general supportive
management of patients with ALF should focus on the prevention
and prompt treatment of infections. Careful monitoring of organ
function and appropriate management of dysfunction as early as
possible should be carried out, as described in subsequent sections on specific organ support.
The progression risk of HE must be recognised and emphasised, and appropriate nursing observations undertaken. The
development of cerebral irritation or change in level of consciousness should be assumed to be HE. However, other causes should
be sought and excluded, such as alcohol withdrawal or other
metabolic causes. There is no evidence for the use of lactulose
or rifaximin in the setting of ALF. Monitoring for neurological
signs of worsening HE should be instituted at 2-hourly intervals.
Development of HE grade 2 or more should result in transfer to a
critical care area, with the skill to provide airway and ventilator
management should the HE deepen. The use of sedative agents
in a ward setting is contraindicated; all such patients should be
transferred to a critical care environment.
Although prolongation of clotting tests is a cardinal feature of
ALF, bleeding is uncommon unless the platelet count is very low,
combined with low fibrinogen, prolongation of activated partial
thromboplastin time (APTT), factor V and INR [111]. Recent
characterisation of the balanced disturbance of both pro- and
anticoagulant factors occurring in patients with ALF, suggests
Table 9. Diagnostic procedures, monitoring and standard care at admission.
Diagnostic tests:
Cultures (respiratory, blood, urine)
Chest X-ray/ECG/liver echography: axial imaging of the abdomen and chest may also be required
Cardiac ECG
Routine monitoring:
Oxygen saturation, blood pressure, heart rate respiratory rate, hourly urine output
Clinical neurological status
Standard care:
Glucose infusions (10–20%): glycemic target ± 140 mg/dl, Na 135–145 mmol/L
Stress ulcer prophylaxis
Restrict clotting factors unless active bleeding
N-acetylcysteine in early stage, even in non-paracetamol cases
Preventative measures:
Avoid sedatives
Avoid hepatotoxic and nephrotoxic drugs
In case of hepatic encephalopathy:
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Transfer to an appropriate level of care (ideally critical care) at the first symptoms of mental alterations
Quiet surrounding, head of bed >30°, head in neutral position and intubate, ventilate and sedate if progresses to >3 coma.
Low threshold for empirical start of antibiotics if hemodynamic deterioration and/or increasing encephalopathy with inflammatory phenotype
In case of evolving HE intubation and sedation prior to the transfer
Ensure volume replete and normalize biochemical variables (Na, Mg, PO4, K)
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that such patients have frequent procoagulant imbalances
[112,113]. Prophylactic administration of coagulation factors is
not advised because it will influence the INR or PT, the most
important factors of prognosis, and is rarely if ever, clinically
indicated.
Patients with ALF are at risk of hypovolaemia due to poor
oral intake, vomiting and vasodilation with an effective decrease
in central blood volume. Fluid bolus therapy and then maintenance fluids may frequently be required but it is essential to
maintain serum sodium in the normal range and avoid excessive fluid overload. Assessment of volume status in a ward environment may be challenging. In the initial phases of hyperacute
and acute presentation, falls in lactate may allow assessment of
volume responsiveness [114]. However, subsequent lactate
reflects a composite measure of both increased production
(peripheral aerobic glycolysis and decreased clearance due to
hepatic metabolic capacity) [115]. Oral intake is encouraged if
the patient is not too nauseated, but if HE progresses this should
be avoided as patients may require urgent intubation. Insertion
of nasogastric tubes prior to intubation is normally avoided due
to risk of vomiting, aspiration, and inducing nasal trauma and
associated bleeding.
Stress ulcer prophylaxis is usually recommended [116,117],
although there is no substantive data to support its use. NAC
has not only been shown to decrease progression to liver injury
if given early following POD (<15 h) [118], but also to have a
beneficial effect on organ dysfunction when given up to 48 h
following POD [49]. The beneficial effects of NAC may be mediated by its putative anti-oxidant attributes, delivery of a
sodium load, anti-inflammatory mechanisms via nuclear factor
kappa B (NFjB), or its vasodilatory effects improving microcirculatory flow [47,119,120]. In non-paracetamol ALF NAC did
not improve survival overall, but did improve outcome in
adults with mild grades of HE [121]. NAC was not shown to
be beneficial in a recent paediatric study, albeit containing significant numbers of patients whose ALF was of metabolic
cause, nor did it show benefit in a subsequent meta-analysis
[122,123]. Animal data suggests that prolonged use of NAC
may limit liver regeneration [124] but there are also studies
suggesting it is beneficial promoting regeneration [125]. In
addition, it is advisable to limit the clinical use of NAC to a
maximum of 5 days duration, given its anti-inflammatory
effects. After this time, functional immune-paresis becomes
increasingly relevant when compared to the initial ALF associated cytokine storm and further functional immunosuppression
is unlikely to benefit the patient and may increase risk of nosocomial sepsis [126,127].
Transfer to a specialised unit
The evolution of ALF is highly unpredictable, especially hyperacute clinical presentations. All patients with a significant ALI
should be considered for transfer to a LTx or tertiary care unit
(Table 10). Even in those who are unlikely to be candidates for
LTx should be considered for transfer to offer improved chances
of survival. ALF is a rare clinical syndrome and the experience
of specialised liver units is required to continually improve
the outcome of these patients. Mental alterations may be subtle. Even mild HE can indicate a life-threatening situation
within a few hours. Therefore, it is advised to consider transfer
at the onset of any mental changes, if the INR is increased >1.5,
or if there is hypoglycemia or metabolic acidosis. Prior to transfer, patient review should be obtained from senior colleagues in
critical care with experience in the transfer of critically ill
patients. In the scenario of an evolving HE, there is an indication for intubation and sedation to ensure a controlled and safe
transfer. Transfer standards should be compliant with those of
critical care societies [128]; appropriate fluids should be available for ongoing volume resuscitation, the patient maintained
normoglycaemic, and vasopressors should be drawn-up and
available. Pupils should be inspected and mannitol carried in
case of the development of fixed dilated pupils in transit.
Detailed guidance and discussion between the transferring
and receiving team is essential, along with the clinical expertise
to deal with acute deteriorations in a clinical condition. The
insertion of central venous lines and arterial lines may be complicated by concerns regarding coagulopathy. Fresh frozen
plasma, cryoprecipitate or factor concentrates should be
avoided as they distort clinical decision making with respect
to prognosis. Data now suggests that largely balanced coagulation disturbances without a bout of bleeding, in conjunction
with isolated prolongation of INR, as well as very low platelets
and fibrinogen, may be associated with an increased risk of
bleeding. If the platelet count is low (<30,000/ll) platelets
may be given before line insertion. If dynamic assessment of
coagulation (thrombo-elastography) is available, this may provide reassurance [111,129]. Initially, patients may be managed
with a radial arterial line and large bore peripheral cannulae.
If there may be a need for vasopressors and the clinicians are
concerned with the risk of an internal jugular line, then a
femoral venous line may be inserted. This allows ease of access,
direct pressure for bleeding and decreased risk of other organ
damage if bleeding occurs. Line insertions should be undertaken by experienced individuals, ideally with ultrasound guidance ensuring the site of venous puncture is well below the
inguinal ligament. Subclavian access should be avoided due to
risk of complications.
Recommendations
Diagnosis of ALF should be always considered with respect
to the full clinical picture; appropriate investigations and
discussion with a tertiary centre should be undertaken.
This is especially important in cases of subacute clinical
course (evidence level III, grade of recommendation 1).
Frequent senior clinical review (twice daily minimum) and
assessment of physiological parameters, blood results and
metabolic status should be carried out (evidence level III,
grade of recommendation 1).
Hourly urine output should be assessed as a marker of
renal function, alongside creatinine (evidence level III,
grade of recommendation 1).
Clinical deterioration with extrahepatic organ involvement should result in transfer to critical care and tertiary
centre (evidence level III, grade of recommendation 1).
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Table 10. Suggested criteria for referral of cases of ALF to specialist units.
Paracetamol and hyperacute aetiologies
Non-paracetamol
Arterial pH <7.30 or HCO3 <18
INR >3.0 day 2 or >4.0 thereafter
Oliguria and/or elevated creatinine
Altered level of consciousness
Hypoglycaemia
Elevated lactate unresponsive to fluid resuscitation
pH <7.30 or HCO3 <18
INR >1.8
Oliguria/renal failure or Na <130 mmol/L
Encephalopathy, hypoglycaemia or metabolic acidosis
Bilirubin >300 lmol/L (17.6 mg/dl)
Shrinking liver size
Coagulation/hemostasis
Neurological = Cerebral oedema
Unbalanced hemostasis
Thrombocytopenia
Infection
Cranial hypertension
Brain death
Acute liver failure
Bacterial, fungal
Pneumopathy
Septicemia
Urinary infection
Metabolic
Hypoglycemia
Hyponatremia
Hypophosphoremia
Hypokalemia
Haemodynamic
Pulmonary
Renal
Hyperkinetic syndrome
Arrhythmia
Pneumopathy
Acute respiratory distress syndrome
Pulmonary overload
Toxic
Functional
Fig. 2. Main organ specific complications in ALF.
Considerations for future studies
Biomarkers to help predict deterioration and likely progression of disease.
Assessment of volume status and appropriate fluids in a
ward setting.
Point of care assessment for sepsis.
Organ specific management (Fig. 2)
Cardiovascular management
Most patients presenting with ALF or severe ALI develop systemic
vasodilation with reduced effective central blood volume. Early
presentation with hyperlactataemia is probably a consequence
of volume depletion, and responds to appropriate volume loading. Thereafter, ongoing hyperlactataemia is likely to reflect the
severity of the underlying liver failure; the liver in unable to
metabolise the increased lactate production seen in response to
sympathetic drive and accelerated aerobic glycolysis (Fig. 2)
[130–133].
1058
In addition to hyperlactataemia, if clinical examination at initial presentation reveals no evidence of cardiorespiratory disease
(e.g., jugular venous pressure not elevated), and the patient has
evidence of end organ dysfunction (peripheral hypoperfusion,
acidosis, oliguria or renal failure,) then it is highly likely that they
are volume depleted and will respond to an appropriate fluid
challenge. There is little evidence supporting the use of any specific fluid for volume loading in ALF. However, general critical care
literature supports the use of crystalloid fluid over colloid
[130–133]. The choice should be guided by biochemical parameters and clinical status; initially normal saline may be effective.
Hyperchloraemia should be avoided, as it has been associated
with increased risk of renal failure and other morbidities
[134,135]. Further crystalloid loading may then be undertaken
with Ringers lactate (recognising the risk of hypotonicity) or a
balanced solution as required. Balanced solutions are buffered
with either bicarbonate or acetate. Although most patients with
cirrhosis can metabolise acetate, those with severe hyperacute
and acute presentations of ALF may have a risk of a decreased
metabolic capacity in this clinical context. The role of albumin
has not been investigated in ALF. Subgroup post hoc analysis in
the Saline vs. Albumin Fluid Evaluation (SAFE) study suggested
a benefit in severe sepsis and septic shock, but detrimental in
patients with traumatic brain injury [136,137]. Patients with
ALF could be considered to phenotypically represent both groups;
a similar trend was reported in the more recent Albios study
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where possible improved outcome in septic shock was seen
[138]. If used in this context, albumin should be viewed more
as a drug, than as a resuscitative solution.
In addition to clinical assessment, support with other imaging
or invasive techniques is often needed to assess whether volume
therapy is adequate. The use of central venous saturation (ScvO2)
to assess volume status in patients with ALF, is not applicable, in
a similar way to the setting of a hyperdynamic circulation [139].
ScvO2 will be elevated even if the patient is volume depleted and
fluid responsive [140]. The purpose of bolus fluid therapy is to
increase stroke volume and subsequently, cardiac output. Assessment of an appropriate increase in cardiac output can be
achieved with either real time ECG, cardiac or oesophageal Doppler; the latter is only applicable in patients who are ventilated.
Use of invasive monitoring (such as pulmonary artery catheter
or pulse contour analysis), provides measures of cardiac index.
Pulse contour analysis also measures volume status and allows
prediction of the likely response to fluid challenge. In ventilated
patients use of inspiratory hold can also be used to assess the
likely response to volume challenge. Passive leg raise, to investigate for an increase in cardiac output in response to a volume
load, is less applicable in the context of high grade HE [141–144].
There are considerable data to suggest that excess fluid and a
persistent positive fluid balance is associated with higher mortality in many patient cohorts. Elevated venous pressure can be
associated with increased tissue oedema and greater impairment
of microcirculatory flow. Elevated right sided cardiac pressures
may be detrimental to liver venous outflow and hence liver function and regeneration, gut integrity and renal functions [145–
147]. Therefore, volume overload should be avoided as much as
volume depletion.
In the cohort of patients with ascites due to subacute liver
failure or acute Budd-Chiari syndrome, elevated intraabdominal pressure may be present. This may alter response to
volume loading, in addition to increasing risk of gut dysfunction
and AKI, response to fluid resuscitation needs to be assessed individually. In patients with elevated right sided cardiac pressures
and ascites, further fluid therapy is likely to have limited or minimal effect on cardiac index. Drainage of some ascites may
improve venous return and improve cardiac index [148].
Following adequate volume loading, persistent hypotension
requires treatment with vasopressors. Given the usual clinical
picture in ALF of an elevated cardiac output and decreased vascular tone, the initial pressor recommended would be norepinephrine, at a starting dose of 0.05 lg/kg/min. Additional low
dose vasopressin (1–2 units/hour), should be considered if norepinephrine requirements increase to >0.2–0.3 lg/kg/min [149].
More recent studies in critical care sepsis cohorts have not shown
any benefit of additional vasopressin [150]. Vasopressin has been
suggested to be detrimental in regard to cerebral complications
in ALF [151]. However, a study comparing terlipressin and norepinephrine did not show any difference regarding intracranial
pressure (ICP) [152]. In patients whose vasopressor requirements
are >0.2 lg/kg/min, arterial pressure monitoring from a central
artery (axillary or femoral) should be considered, as opposed to
a peripheral arterial line in order to ensure accurate measurement. The appropriate blood pressure range to target is highly
controversial and largely without evidence. In young patients
without pre-existing hypertension, a mean arterial pressure
(MAP) of 60 mmHg is more than adequate. In patients who are
at risk of AKI there is some evidence that a MAP >75 mmHg
may be better in those with chronic hypertension [153]. However, once RRT has been established, there is no evidence to support that maintaining this higher MAP is beneficial [145,154–
156]. Furthermore, other studies have not shown this relationship, and aiming for higher MAP was associated with increased
drug related events [157,158]. A recent randomised trial of blood
pressure goals failed to demonstrate any benefit for higher perfusion pressures, except in decreasing AKI in those patients with
pre-existing hypertension. In those patients where a higher
MAP was achieved, there was an increased incidence of atrial fibrillation [156].
Although most patients with ALF will have a hyperdynamic
circulation, a proportion of those with hypoxic hepatitis will have
evidence of both right and left sided cardiac dysfunction, with or
without valvular heart disease. In this setting, optimisation of
cardiac function will need to be individualised, regarding volume
status and inotropic needs. Right sided pressures should be minimised to facilitate optimal hepatic venous drainage alongside
effective left ventricular function. Adequate MAP will need to
be achieved with a vasopressor such as norepinephrine, to ensure
adequate coronary perfusion pressure. In those with evidence of
pulmonary hypertension, specific management is required. A
negative fluid balance should be achieved in those with pulmonary venous hypertension or central volume overload. In
patients with pulmonary arterial hypertension, control of CO2 is
essential and treatment with prostaglandins and sildenafil may
be beneficial. Pulmonary artery flotation catheters may be
required in combination with cardiac ECG to optimise therapeutic endpoints. Inotropic agents are frequently required; dobutamine or a phosphodiesterase inhibitor such as milrinone, with
later administration of levosmendin should be considered. The
dosage of such agents requires careful titration in the context
of ALF; initiating doses should be very low and without bolus
at commencement. In patients with profound and reversible
acute cardiac dysfunction, extracorporeal support with venoarterial extracorporeal membrane oxygenation (VA ECMO) may
be appropriate [159]. This should only be undertaken in specialised cardiac and liver centres with appropriate expertise. Furthermore, hypoxic hepatitis is a secondary form of ALF and as
such, the primary presenting organ failure needs to be addressed
and managed to facilitate liver recovery. LTx is not indicated.
Whether there is a benefit of giving physiological doses of
hydrocortisone to those ALF patients with vasopressor resistant
shock is not clear. There are no mortality studies, although there
is evidence of adrenal dysfunction in more than 50% of cases with
ALF when tested using a standard ACTH stimulation test. One
study suggested that use of steroids decreases vasopressor
requirements and prolongs time to death, perhaps providing time
to obtain a suitable liver for transplantation [160–162]. If this
therapy is considered, then potential benefits may be offset by
the increased risk of sepsis and reactivation of viral infections
(e.g., CMV and herpes simplex virus). If an ACTH stimulation test
is undertaken, then a supraphysiological response should lead to
the withdrawal of additive steroids as increased mortality has
been reported in patients with septic shock [163]. Recent data
from the Leuven group provide further insights into adrenal dysfunction in critical illness. Namely, increased cortisol availability
appears to be secondary to reduced liver and kidney catabolism
[164,165]. A variety of hormonal and hypothalamic-pituitary axis
abnormalities can be detected and tracked in critically ill
patients, including those with ALF. At present there is a lack of
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clarity as to the meaning of these measures, and thus far, therapeutic manipulation has not been shown to be beneficial [166–
168].
A study from the USA ALF group has shown that elevated troponin is predictive of poor outcome[169], although a subsequent
study did not repeat this finding [170].The observed elevations of
troponin are likely to represent myocyte stress in the setting of
metabolic disarray and multiple organ failure.
Recommendations
Most patients are volume depleted at presentation and
require crystalloid volume resuscitation (evidence level
II-1, grade of recommendation 1).
Persistent hypotension requires critical care management,
with application of vasopressive agents guided by appropriate monitoring techniques (evidence level II-3, grade
of recommendation 1).
Norepinephrine is the vasopressor of choice (evidence
level III, grade of recommendation 1).
Volume overload is as detrimental as underfilling (evidence level II-2, grade of recommendation 1).
Hypoxic hepatitis will require consideration of inotropic
agents (evidence level II-3, grade of recommendation 1).
A blood pressure target has not been defined in the literature (evidence level III, grade of recommendation 2).
Hydrocortisone therapy does not reduce mortality but
does decrease vasopressor requirements (evidence level
II-1, grade of recommendation 1).
Considerations for future studies
Accurate assessment of volume status with biomarkers for
congestion and depletion.
Studies of microcirculatory status as an endpoint for
resuscitation as opposed to pressures.
Appropriate utilisation of VA ECMO in subgroups of
patients with ALF and hypoxic hepatitis.
Recommendations
Standard sedation and lung protective ventilator techniques should be utilised in patients with ALF (evidence
level II-3, grade of recommendation 1).
Respiratory management
Invasive airway management is required in the face of progression to high grade HE to ensure airway protection. In a small
proportion of patients with ALF, ventilatory support may also
be required for hypoxia and respiratory failure. Non-invasive
ventilator support should be avoided in those patients at risk
of HE or with profound metabolic disarray, because of the
high risk of neurological deterioration, aspiration and poor
compliance.
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Standard techniques for intubation should be utilised, as
guided by specialist critical care societies, with adaptations
to account for the brittle haemodynamics and risk of cerebral
oedema observed in ALF. Sedation is normally undertaken
with a short acting opiate and propofol. Although the latter
agent has the potential to decrease blood pressure if the
patient is not volume replete, it has beneficial effects with
respect to decreasing cerebral metabolic rate for oxygen as
well as anticonvulsant properties. Ventilatory settings should
be protective; low tidal volume and appropriate levels of positive end expiratory pressure (PEEP) should be utilised to
maintain an open lung with low tidal volume [171,172].
Hypercarbia and hypocarbia should be avoided, with CO2 targets of between 4.5 and 5.5 kPa (34–41 mmHg). Tidal volumes
should be maintained at 6 ml/kg/ideal body weight, with a
maximum of 8. The incidence of acute respiratory distress
syndrome (ARDS) or acute lung injury is relatively rare in
patients with ALF, and does not appear to contribute to mortality [173]. Care of the airway, appropriate use of physiotherapy and patient positioning should decrease the risk of
ventilator associated pneumonia. Secretions should be sampled
regularly using non-directed broncho-alveolar lavage, and sent
for culture.
Ventilator techniques in patients who develop ARDS are
beyond the scope of these guidelines. However, there is no evidence to support use of oscillation, and although prone ventilation does improve oxygenation and potentially mortality, its
use requires detailed discussion in ALF patients at risk of cerebral
complications [174,175]. High levels of PEEP (>12) should be
monitored regarding transmitted pressure risk with middle cerebral artery Doppler. The balance of hypoxia, hypercarbia and risk
of increased ICP must be individualised at the bedside. In a small
cohort, consideration may be given to venous-venous ECMO, with
use only being advised in centres with expertise in both ALF and
ECMO.
Assessment of the aetiology of hypoxaemia can be difficult. In
some patients with hypoxic hepatitis there is evidence of hepatopulmonary syndrome [176] and this should be excluded with
bubble ECG. In a few cases, there may also be evidence of a toxic
liver syndrome with increased lung water and ARDS. Assessment
of lung water may facilitate optimal management of these
patients. In some patients with significant ascites, the presence
of intra-abdominal hypertension may result in significant
hypoxia [177], and may be alleviated by limited volume paracentesis.
Avoid of excessive hyper or hyocarbia (evidence level III,
grade of recommendation 1).
Regular chest physiotherapy should be carried out and
ventilator associated pneumonia avoided (evidence level
III, grade of recommendation 1).
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Consideration for future studies
Application of extracorporeal lung support techniques to
address risk benefit in highly specific subgroups of
patients.
Gastrointestinal management
Oral nutrition should be encouraged in patients with ALI. Progressive HE or anorexia is likely to result in decreased calorie
intake. Consideration may be given to insertion of a nasogastric
tube to facilitate enteral feeding. Risk and benefit needs to be
assessed at an individual level. The potential risks include causing
bleeding during placement and large gastric residue, with microaspiration if HE progresses.
Guidance regarding nutritional needs in patients with ALF is
largely empirical. Calorie and protein requirements are as per
critically ill populations of other aetiologies. Studies suggest
predicted calorie requirements are slightly underestimated by
standard tools [178–180]. Ammonia monitoring may be useful
during commencement of enteral feeding to ensure that there
is no associated increase. Failure of gastric emptying may be
addressed through placement of a post pyloric feeding tube,
but small bowel failure is more difficult to diagnose. Development of ileus and risk of non-occlusive ischaemia may be associated with gut bacterial translocation. The decision to
introduce total parenteral nutrition (TPN) should be based
upon baseline nutritional status and duration of low calorie
intake. Recent studies have not demonstrated any benefit to
instituting TPN prior to day 5 to 7 post critical care presentation [181–183].
Patients with ALF have increased resting energy expenditure,
which is similar to other critically ill patients. Clinically this is
infrequently measured, but has been reported to be increased
by 18 to 30% compared with normal controls [184,185]. Early
introduction of enteral feeding will minimise loss of muscle mass
and reduce the risk of gastrointestinal haemorrhage. A European
survey of nutritional support in patients with ALF revealed that
25 of 33 responding units used parenteral nutrition [178]. Lipid
emulsions appear safe; LCT/MCT emulsions are the most commonly utilised. In some patients with significant mitochondrial
dysfunction, lipid loads will not be metabolised and may accumulate compounding liver injury. This may especially be the case
when propofol is utilised in high doses as a sedative agent. Therefore, monitoring of lipid profile along with creatinine kinase is
required, targeting serum triglycerides at a concentration
<3.0 mmol/L. Furthermore, patients with ALF release free fatty
acids into the splanchnic circulation, in contrast with normal controls or patients with sepsis [186]. Profound alterations in circulating amino acids are reported in patients with ALF,
characterised by increased tryptophan and its metabolites, aromatic and sulphur containing amino acids and reduced branch
chain amino acids leucine, isoleucine and valine. Excessive infusion of amino acids may aggravate the hyperammonaemia that
is characteristic of ALF and precipitate cerebral oedema and
intracranial hypertension. This may be avoided by regular monitoring of plasma ammonia during both enteral and parenteral
nutrition.
There is a moderate risk of pancreatitis in patients with acute
and hyperacute phenotypes and axial imaging to quantify this
may be required if there is clinical suspicion. Management is as
per other critical care settings. The finding of severe pancreatitis
is a relative contraindication to emergency LTx.
Proton pump inhibitors (PPI) are normally administered,
although the evidence base for their use is based on risk
factors of organ failure and coagulopathy. This, however,
should be balanced against the risk of ventilator associated
pneumonia and Clostridium difficile infection [187]. PPIs
should normally be discontinued when enteral nutrition
has been established.
Recommendations
Patients with ALF have increased resting energy
expenditure. Therefore, enteral or parenteral nutrition
are warranted (evidence level II-3, grade of recommendation 1).
Avoid nasogastric feeding in those with progressive
encephalopathy (evidence level III, grade of recommendation 1).
Monitor ammonia when instituting enteral nutrition
(evidence level III, grade of recommendation 1).
PPI administration should be balanced against the risk of
ventilator associated pneumonia and Clostridium
difficile infection (evidence level II-3, grade of recommendation 1).
Consider stopping PPI when enteral feeding has been
established (evidence level III, grade of recommendation 1).
Consideration for future studies
Biomarkers for small bowel ileus and failure.
Metabolic management
ALF is frequently associated with electrolyte and metabolic disturbances, which are more common in patients with hyperacute
ALF, especially when associated with AKI [14]. Hypoglycaemia is
a well recognised complication of ALF and is multifactorial in
pathogenesis; increased hepatic extraction of glucose, increased
hepatic glycolysis and impaired gluconeogenesis, with failure of
compensatory renal gluconeogenesis have all been reported
[14]. The frequency of hypoglycaemia requiring treatment is
increased in patients with paracetamol induced ALF and AKI
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(55%) compared with patients without AKI (22%) [27,188]. The
clinical features of hypoglycaemia may be confused with developing HE. Therefore, frequent monitoring of blood glucose is
required in patients with ALF, especially hyperacute cases, where
‘‘BMstix” monitoring should be undertaken every 2 h. Rapid
boluses of concentrated glucose may induce large osmotic shifts
in intravascular and cerebral compartments and should be
avoided, but may be necessary to treat critical hypoglycaemia.
Hypoglycaemia is predictive of developing AKI and is associated
with increased mortality [189]. Hyperglycemia can exacerbate
raised ICP and should be avoided. Tight glycaemic control with
infusion of insulin may reduce mortality in the critically ill, with
targets of blood glucose between 8.3–10.0 mmol/L (150–180 mg/
dl) [190–193]. However, a recent meta-analysis of patients in
neurological critical care suggested outcomes were only
improved with higher glucose concentrations (>200 mg/dl;
11.1 mmol/L) as the threshold for insulin administration
[194,195].
Hyponatraemia is also relatively common in patients with
ALF, especially hyperacute cases. Previously data reported that
32% of cases with paracetamol induced ALF had serum sodium
<130 mmol/L [185,197]. There is a correlation between serum
sodium and ICP. Infusion of hypertonic saline to maintain
serum sodium between 145 and 155 mmol/L compared with
standard of care resulted in reduced ICP and less requirement
for bolus therapy for sustained episodes of raised ICP. A
decrease in vasopressor requirement was also observed during
the first 36 h of infusion [198]. These data suggest that
hyponatraemia should be avoided, and maintaining relative
hypernatraemia with infusion of hypertonic saline can prevent
raised ICP. However, serum sodium levels above 150 mmol/L
may be associated with cell damage and should be avoided.
Therefore, fluid resuscitation and hypertonic saline infusions
should be targeted to maintain sodium at 140–145 mmol/L.
Rapid change in sodium levels should also be avoided and
correction should be correlated to the rate of drop, which
should not exceed 10 mmol/L per 24 h [199]. The observed
benefits of NAC in ALF may have been attributable to the
effect of a sodium load [47,200]. RRT can also be utilised to
correct hyponatraemia, facilitate fluid balance and control of
acidosis [201].
Acidosis, increased circulating lactate and reduced bicarbonate are common features in patients with hyperacute and acute
ALF, and are multifactorial in pathogenesis, with increased systemic production and reduced hepatic clearance reported
[131,186,200]. Acidosis is less common in subacute ALF syndromes, possibly due to the alkalinising effect of hypoalbuminaemia [202]. Both acidosis and increased lactate have been
proposed as prognostic markers in paracetamol induced ALF. It
is likely they are also applicable in other forms of hyperacute
liver failure. RRT was utilised in the majority of patients where
lactate was identified as an additional possible prognostic marker
[130], and therefore RRT should not be withheld when managing
patients with ALF or ALI.
Alterations in serum phosphate, magnesium, ionised calcium
and potassium are commonly observed and should be monitored
and corrected, as clinically appropriate. Hypophosphatemia is a
favourable prognostic sign and appears to be associated with
liver regeneration [203]. Careful replacement therapy is required,
however, to avoid the potentially serious organ dysfunction associated with hypophosphataemia.
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Recommendations
Stringent attention to detail and normalisation of biochemical abnormalities is warranted in patients with ALF
(evidence level III, grade of recommendation 1).
Hypoglycemia is common in patients with ALF, is associated with increased mortality and needs to be corrected
avoiding hyperglycemia (evidence level II-3, grade of recommendation 1).
Hyponatreamia is detrimental to outcome and should be
corrected to maintain concentrations 140–150 mmol/L
(evidence level II-2, grade of recommendation 1).
Lactate elevation is related to increased production and
decreased clearance, and remains a poor prognostic
marker. RRT is indicated to correct acidosis and metabolic
disturbances (evidence level II-3, grade of recommendation 1).
Acute kidney injury and renal replacement therapy
AKI is common in patients with ALF. The two most common classifications are represented by RIFLE and AKIN, but have recently
been updated by the Kidney Disease: Improving Global Outcomes
(KDIGO) AKI working group [204–206]. The general acceptance of
a classification for AKI in patients with ALF will significantly
improve studies of epidemiology, prevention and treatment in
this context. Revised consensus recommendations for diagnosis
and management of AKI in cirrhosis, largely based on KDIGO criteria have recently been proposed by the International Club of
Ascites [207]. Their assessment in patients with ALF would be
certainly warranted and compared with KDIGO/ADQI for AKI in
sepsis and MOF.
Between 40 and 80% of ALF patients referred to tertiary
liver units are classified as having AKI, which is associated
with increased mortality and length of hospital stay. Risk
factors for AKI include increased age, paracetamol-induced
ALF, hypotension, the presence of the systemic inflammatory
response syndrome (SIRS) and infection [197,208]. Strategies
to prevent the development of AKI include: correction of
hypotension, prompt treatment of infection, avoiding nephrotoxic medications and judicious use of radiological procedures
that require intravenous contrast; albeit balancing risks and
benefits of contrast radiology and aminoglycosides in any
given clinical context.
The timing of institution of RRT in the context of ALF has the
potential to cause conflict between speciality groups involved in
the care for these patients [209]. RRT is normally instituted in the
context of uraemia, fluid overload and hyperkalaemia. In the context of ALF, however, RRT may be offered to manage acidosis,
hyperammonaemia and sodium imbalance, facilitate temperature and metabolic control and, as such, may be better referred
to as liver or metabolic replacement therapy. Slack et al. have
shown a clear correlation between creatinine clearance and
ammonia clearance [210]. Therefore, early consideration of RRT
should be undertaken in those ALF patients with markedly elevated ammonia and, or progressive HE.
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Continuous modes of RRT are preferred to intermittent
dialysis. These therapies avoid the large metabolic and haemodynamic fluctuations associated with intermittent dialysis,
which could precipitate raised ICP [8,211]. Lactate free buffers
accelerate correction of acidosis. Anticoagulation for dialysis is
the subject of much debate; options include no anticoagulation,
prostacyclin and regional citrate, with little data to recommend
which is the safest and most efficacious in patients with ALF.
Some data would suggest that although patients with cirrhosis
will tolerate citrate anticoagulation, patients with acute and
hyperacute ALF may be less able to metabolise the citrate load
[212]. If citrate is used in the context of ALF, close monitoring
of total calcium compared with ionised calcium is required
[213,214].
Most ALF patients with AKI will fully recover renal function
either by the time of hospital discharge or following LTx [197].
Predictive factors for complete renal recovery following
paracetamol ALF include: female gender, lower model for endstage liver disease (MELD) scores at day 3, patients with
admission hypotension and patients with lower grades of AKI
[189,208]. Isolated renal failure without ALF is seen in some
cases of POD and can normally be managed with intermittent
haemodialysis [215].
Recommendations
Early institution of extracorporeal support (RRT) should be
considered for persistent hyperammonaemia, control of
hyponatraemia and other metabolic abnormalities, fluid
balance and potentially temperature control (evidence
level III, grade of recommendation 1).
Anticoagulation of RRT circuits remain a matter of debate,
and close monitoring of metabolic status should be undertaken if citrate is utilised (evidence level II-2, grade of
recommendation 1).
Continuous RRT should always be undertaken in the critically ill patient with ALF as opposed to intermittent
haemodialysis (evidence level III, grade of recommendation 1).
Considerations for future studies
Monitoring and management of anticoagulation of extracorporeal circuits.
Appropriate indications for commencing RRT.
Biomarkers for the prediction of and recovery from AKI.
with ALF. However, this abnormal coagulation is not translated
into an increased risk of bleeding [111]. Recent, in depth analysis
of coagulation abnormalities in patients with ALF have suggested
that most patients have rebalanced haemostasis; most patients
have a ‘‘normal coagulation state”, despite prolongation of
measured INR or PT, and a significant proportion are hypercoagulable. This is related to significant increases in endogenous
heparinoids, procoagulant microparticles, von Willebrand factor
and factor VIII, reduced pro- and anticoagulant factors and
release of ‘‘younger” more reactive platelets in patients with
ALF [112,113,216–218]. Some of these changes may have prognostic significance, but surprisingly there does not appear to be
any significant differences between hyperacute and other
aetiologies of ALF. Monitoring of coagulation in patients with
ALF requires standard and extended laboratory techniques
(thrombin generation, factor VIII, etc.) in addition to thromboviscous technology, which should increasingly become a standard
additional measure.
Appreciation of this balanced haemostasis reinforces the recommendation that prophylactic correction of coagulation or platelet levels is not necessary. It may instead adversely affect
prognostication as well as increase the risk of thrombosis or
transfusion related acute lung injury in patients with ALF. Arguably there are only two situations that require active management of coagulation and platelets. Firstly, insertion of ICP
monitors requires infusion of fresh frozen plasma, cryoprecipitate
and platelets depending on the initial assessment of coagulation,
as guided by neurosurgical specialist societies. Others have suggested prophylactic recombinant factor VIIa prior to insertion of
ICP monitors, but there is no evidence of decreased mortality
and a potential significant risk of thrombosis [217–221]. Secondly, significant active haemorrhage necessitates correction of
coagulation and thrombocytopenia, in addition to identification
and local measures to deal with the source of the bleeding.
Although indications in the specific setting of ALF are not available, it seems reasonable to target plasma fibrinogen levels 1.5–
2 g/L by infusing fibrinogen concentrate at an initial dose of
25–50 mg/kg body weight, and a platelet count >60,000/ll
[222]. The role of additional supportive therapies such as tranexamic acid should also be considered in this context.
An appropriate level of haemoglobin is usually agreed to be
greater than 7 g/dl, although adaptation may be considered in
the context of severe cardiorespiratory failure or subarachnoid
haemorrhage [223].
Recommendations
The routine use of fresh frozen plasma and other coagulation factors is not supported, and should be limited to
specific situations, such as insertion of ICP monitors or
active bleeding (evidence level II-3, grade of recommendation 1).
Haemoglobin target for transfusion is 7 g/dl (evidence
level II-2, grade of recommendation 1).
Coagulation: Monitoring and management
Disordered coagulation is an essential diagnostic component of
ALF. Rapid changes in the PT or INR are characteristic and of
significant prognostic value. Thrombocytopenia, reduced circulating pro- and anticoagulant proteins and increased PAI-1
(favouring fibrinolysis) are all commonly reported in patients
Venous thrombosis prophylaxis should be considered in
the daily review (evidence level III, grade of recommendation 1).
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Considerations for future studies
Role of anticoagulation to improve microcirculation and
decrease liver injury.
Further understanding of coagulation disturbances and
critically ill patients with ALF and point of care
monitoring.
Risk of thrombotic complication in the context of ALF and
appropriate therapeutic interventions.
Sepsis, inflammation and anti-inflammatory management
Bacterial, fungal and viral infections: Incidence, timing and nature
Patients with ALF are at increased risk of developing infections, sepsis and septic shock. Infectious complications were
a leading cause of death in ALF [224–226] although recent
data suggest bacteraemia is not independently predictive of
mortality [227]. Severe, untreated infection may preclude LTx
or complicate the postoperative course. Patients with ALF have
multiple immunological alterations [228–230] and an
increased requirement for invasive organ support or monitoring, which contributes to colonisation with multi-drug resistant bacteria and the development of nosocomial sepsis.
Bacterial infections have been documented in 60–80% of
patients; most commonly pneumonia (50%), urinary tract
infections (22%), intravenous catheter-induced bacteraemia
(12%), and spontaneous bacteraemia (16%). Gram-negative
enteric bacilli and Gram-positive cocci are the most frequently
isolated [224,225]. More recent data has suggested infection,
such as bacteraemia, occur later after admission (median
10 days compared with 3 days in earlier studies), and Gramnegative organisms are now more common isolates than
Gram-positive bacteria [227]. Furthermore, recent publications
highlight the high frequency of infection with either methicillin resistant Staphylococcus aureus and vancomycin resistant
Enterococcus [227]. Fungal infections occur in about one-third
of patients requiring prolonged critical care support with
ALF, largely with candida species. These patients frequently
have concurrent bacterial infection. Viral infections and reactivation of CMV is common in critically ill patients [231,232]
and is likely to be present in ALF, albeit poorly reported in
the literature.
Absolute attention to hand washing, and care of extraneous
monitoring devices such as urinary catheters, venous and
arterial cannulae and appropriate bronchial toilet are
essential. Strict asepsis should be utilised when lines are
manipulated.
Diagnosis of infection
The diagnosis of infection in patients with ALF is difficult; the
clinical features are non-specific and examinations such as C
reactive protein and procalcitonin measurements are frequently
unhelpful. A high level of clinical suspicion of infection should
be maintained in patients with ALF [233,234]. Routine microbi-
1064
ologic surveillance can result in early detection and treatment
of infections [224]. Admission and frequent screening of blood,
urine and appropriate samples for cultures should be performed as clinically indicated. Admission HE and SIRS score
>2 are significant predictors of bacteraemia, and deterioration
of mental status, unexplained fever and leukocytosis (particularly in patients with paracetamol toxicity), may represent
the onset of infection [227]. Deterioration in hepatic coma
grade after initial improvement, pyrexia unresponsive to antibiotics, established renal failure, and marked elevation in white
cell count should prompt aggressive investigation for fungal,
bacterial or viral infection. This is especially important in
patients already on broad spectrum antibiotics. Use of
biomarkers for fungal infection should be utilised, whilst recognising their high false positive rate, but low risk of false negative results [235].
Treatment vs. prophylaxis and infection control standards
Broad spectrum antibiotics are generally used to cover common
organisms such as Staphylococcal species, Streptococcal species,
or Gram-negative rods. Empirical broad spectrum antibiotics
should be administered to patients with ALF who have signs of
SIRS, refractory hypotension or unexplained progression to
higher grades of HE [10].
Prophylactic parenteral antimicrobial therapy reduces the
incidence of infection in certain groups of patients with
ALF. However, survival benefit has not been shown [236].
Selective bowel decontamination using non-absorbable antibiotics and parenteral antibiotics also do not impact survival
[237]. An association of infection and SIRS with progression
to deeper stages of HE has been reported [226,238], and a
reduction of infection and SIRS may have an impact on ICP
[239–241]. However, there are no controlled trials confirming
that the use of prophylactic antimicrobials decreases the likelihood of progression of HE or the development of raised ICP.
Therefore, there is not sufficient data to support a generalised
antibiotic prophylaxis practice in ALF [236]. Empiric antibiotics are recommended for patients listed for super urgent
LTx, since the development of infection and sepsis may
prompt delisting.
Decisions surrounding antimicrobial choice should be based
on knowledge of local microbiological data.
Association of SIRS and organ dysfunction
ALF is associated with dynamic immune dysfunction. An
altered balance between opposing systemic pro- and antiinflammatory immune profiles can contribute to organ failure
and death in ALF, irrespective of aetiology [44,228,239,242–
247]. Liver injury due to any type of insult leads to: the activation of the innate immune system, altered macrophage
function, impaired neutrophil function, initial activation of
the complement system (and thence marked reduction in
complement levels), impaired phagocytosis and opsonisation
resulting in functional immunoparesis. Liver cell death leads
to a release of pro-inflammatory mediators, which may be
associated with elimination of pathogens and tissue regeneration. However, they may also be associated with the
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mediation and propagation of further tissue damage. Local tissue injury and inflammatory responses are associated with a
‘‘spill over” phenomenon of chemotactic mediators and proinflammatory cytokines, which subsequently leads to the
recruitment of monocytes, lymphocytes, and polymorphonuclear leukocytes [218,248–252]. These cells secrete vasoactive
mediators, which activate both platelets and the coagulation
cascade, and further increase vascular permeability alongside
microcirculatory failure and thrombosis [113,218]. This process
leads to SIRS. Release of damage associated molecular patterns, e.g., HMGB1, from injured hepatocytes may also contribute to the development of SIRS [246]. SIRS leads to a
vicious cycle wherein an increase in vascular permeability further contributes to tissue injury. Over time, the balance tilts
towards the anti-inflammatory response, which is associated
with immune suppression, recurrent infections, sepsis, and
death [243].
SIRS appears to be involved in the worsening of HE,
reduces the chances of transplantation and confers a poorer
prognosis, independent of infection [44,226]. In a timecourse study, the appearance of SIRS occurred earlier and with
a greater magnitude in patients with severe paracetamolinduced hepatotoxicity who died, compared with surviving
patients [253]. Similarly, the development of SIRS preceded
the development of organ failure, and increased SIRS scores
was associated with increased SOFA scores and risk of mortality [208,254].
There is an association between infection and SIRS. Early
studies suggested infected patients were more likely to develop
SIRS, and the extent of their physiological disturbance was
greater than that of uninfected patients, although recent publications question this [227,238]. Arterial lactate levels correlate
with the SOFA score and the number of SIRS components
[253]. Inflammation also plays a synergistic role in the pathogenesis of high grade HE and raised ICP because of its effects
on cerebral blood flow (CBF) and activation of brain inflammation [255–259]. Inflammatory markers, arterial ammonia, and
CBF were higher in patients with poor prognosis, and TNFalpha levels correlated with CBF [238]. Inhibition of brain
inflammation in animal models results in decreased brain water
and reduced ICP [260–262].
Potential biomarkers in ALF: Cytokines, HLA-DR, and cell death
serum markers
There is still a need to identify ALF-specific and dynamic
biomarkers that can be used for follow-up and for determining outcome. Expression of HLA-DR and markers of apoptosis
have been suggested as biomarkers of ALF. The percentage
of monocyte HLA-DR expression is lower in patients with
ALF when compared to healthy volunteers or patients with
chronic liver disease. It correlates with INR, blood lactate,
pH, and levels of encephalopathy, predicting poor prognosis
[241,263] as do markers of inflammation and coagulation
[264,265]. The measurement of caspase-cleaved and uncleaved
cytokeratin-18 is an early predictor of survival in severe septic
patients with hepatic dysfunction [249,266]. Patients who
spontaneously recover from ALF revealed a significantly higher
level of activation of caspases than those who required transplantation or died [267,268]. Acetylated HMGB1 secreted from
activated macrophages may also aid in prognostication
[248,269].
Recommendations
Prophylactic antibiotics, non-absorbable antibiotics, and
antifungal have not been shown to improve survival in
ALF (evidence level II-2, grade of recommendation 1).
Regular periodic surveillance cultures should be performed in all patients with ALF (evidence level III, grade
of recommendation 1).
Early anti-infection treatments should be introduced upon
appearance of progression of hepatic encephalopathy,
clinical signs of infections, or elements of SIRS (evidence
level II-3, grade of recommendation 1).
Antifungal therapy in those with prolonged critical care
support for multiple organ failure should be considered,
as guided by the use of biomarkers (evidence level II-3,
grade of recommendation 1).
Considerations for future studies
Integration of inflammatory biomarkers with biochemical
and functional markers of liver function.
Biomarkers to separate infection and inflammation.
Immunomodulatory therapy to promote liver regeneration and decrease nosocomial sepsis.
The brain in ALF
Neurological manifestations
HE is an essential manifestation of ALF, characterised by a
decrease in the level of consciousness and altered neurotransmission. HE tends to fluctuate and may progress from a trivial
lack of awareness to deep coma. Additional manifestations
may include headache, vomiting, asterixis, agitation, hyperreflexia and clonus [196]. The diagnosis of HE is clinical and
requires the exclusion of other causes of neurological
disturbance (e.g., hypoglycemia, hypercapnia, non-convulsive
seizures, stroke, encephalitis, effect of sedatives and other
causes). One characteristic manifestation of ALF is the development of clinically significant brain oedema and intracranial
hypertension (ICH). These can manifest as a result of arterial
hypertension, bradycardia and mydriasis in patients who have
progressed to grade 3 or 4 coma. The course of HE is dictated
by the outcome and phenotype of liver failure, and usually
parallels the evolution of other parameters of liver function.
Additional factors that may worsen the neurological outcome
are the coexistence of infection or presence of inflammation
without sepsis alongside the presence of other organ failure
[8,226,255,259,270].
Principles of care for patients with a low level of encephalopathy
Regular clinical and mainly neurological examination is mandatory in order to detect early signs of HE and progression to high
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grade encephalopathy (grade 3 and 4). Patients should be managed in a quiet environment with regular monitoring and management of other parameters, with especial attention directed
to serum sodium as previously discussed. Although ammonia
reducing strategies may be of benefit, the role of conventional
treatments for HE (lactulose and rifaximin) have no evidence
base in ALF. Lactulose may be associated with increased risk of
ileus and bowel dilation.
Management of the patient with altered Glasgow Coma Scale (GCS)
Once the patient progresses to grade 3 HE, the general practice at transplantation centres is for intubation and mechanical ventilation; measures that protect the airway prevent
aspiration and provide safer respiratory care [10]. Grade 3
coma, in the context of ALF and its management, is not
defined by a hepatic flap but the development of marked agitation and frequent aggression with a decrease in GCS (GCS
usually E1-2, V 3-4 and M4). Progression to grade 4 coma is
associated with marked reduction in GCS (E1, V 1-2 and M1-3)
[14]. Ventilatory management, specifically related to cerebral
protection, includes: minimising the risk of pulmonary barotraumas, aiming for a partial pressure of carbon dioxide
(PaCO2) between 4.5–5.5 kPa (34–42 mmHg) and use of propofol as a sedative agent. This may protect from ICH and reduce
the risk of seizures [271]. A short acting opiate should be
added to provide adequate analgesia. In case of concern of seizure activity, EEG monitoring should be undertaken and
antiepileptic drugs administered; however, the prophylactic
use of antiepileptic drugs is not warranted [272]. Phenytoin
has traditionally been the medication of choice; however,
agents without risk of hepatotoxicity and more easily achieved
therapeutic levels such as levetiracetam or lacosamide are
now more frequently utilised.
Intracranial hypertension
Brain oedema that causes ICH is a classically described complication of HE in ALF. Though the incidence of ICH has decreased
recently, it still may affect one-third of cases who progress to
grade 3 or 4 HE [8]. Patients at a higher risk of ICH are those with
a hyperacute or acute phenotype, that is a shorter jaundice-toencephalopathy interval [4], younger age (likely related to
decreased available free space within the cranium), renal impairment (associated with increased ammonia and an inflammatory
phenotype) and need for inotrope support (frequently associated
with an inflammatory phenotype [259]. Persistent elevation of
arterial ammonia (>200 lmol/L) levels, especially following initial management, also indicate an increased risk of ICH
[259,273,274] whilst decreasing values represent a lower risk
[275]. The physical signs defined at clinical examination (pupil
dilation, fixed or sluggish response to light and sustained hypertension) are not sensitive enough to predict changes in ICP. Brain
imaging may be more reliable, but CT scans are relatively insensitive to actual ICH and moving patients with severe HE can lead
to surges of ICP. For this reason, scans are not recommended for
monitoring brain oedema and are reserved for diagnosing
intracranial bleeding or cerebral herniation with absent
perfusion.
ICP monitoring provides the gold standard for measurement
and monitoring of ICP and hence management of pressure
1066
surges. However, its use does not seem to modify patients’ outcomes [220,276,277] and is associated with clinical risk, since
bleeding within the cranium combined with brain oedema
can lead to significant morbidity and mortality. Therefore,
placement of ICP devices remains a matter of intense debate,
with their use reserved for patients at high risk of ICH, and
in centres with large neurosurgical experience in ALF management [278–280].
Several non-invasive techniques have been proposed to
estimate ICP, but all are complex and demonstrate considerable ‘‘inter and intra-assay” variability. Changes in CBF
reflecting ischaemia and vasodilation of the cerebral circulation and resistance to flow, with increased ICP, can be
assessed using middle cerebral artery Doppler [281]. An
increase in CBF usually precedes the rise of ICP. Indirect data
can be obtained by monitoring reverse jugular vein oxygen
saturation; values over 80% usually indicate hyperaemia and
under 55% relative ischaemia. The latter suggests a scenario
where cerebral oxygen consumption is in excess of supply
due to epileptiform activity (increased demand) or inadequate
supply (hyperventilation and hypocapnia, inadequate blood
pressure or cardiac index). The measurement of optic nerve
depth is also representative of ICP, according to a recent
assessment [282].
Therapeutic options for raised intracranial pressure
General measures include elevation of the head at a 30-degree
upright angle, avoidance of fever, hypoglycaemia or hyperglycemia and clamping of serum sodium at 140–145 mmol/L. In
patients who are monitored for ICP, pressure should be maintained below 20–25 mmHg and the difference between MAP
and ICP (cerebral perfusion pressure, CPP) should remain above
50 mmHg [283]. However, in all such clinical scenarios, individualised treatment must be implemented because an increase in
MAP is often associated with an increase in CBF and hence ICP.
As a result, survivors with protracted low CPP have been reported
[284].
Sustained surges in ICP (>25 mmHg) or development of
clinical signs should be treated by a bolus of hypertonic saline (200 ml, 2.7% or 20 ml, 30%) [199] or intravenous mannitol (150 ml, 20%) given over 20 min [285], in addition to
ensuring optimal sedation. In a resistant scenario, a short
period of hyperventilation may be required, reducing arterial
PaCO2 to 25–30 mmHg. Steroids are not recommended [285].
It is essential that serum osmolarity is maintained below 320
mOsmol and RRT may frequently be required to facilitate
this.
In situations where the patient has cerebral hyperaemia
and signs of ICH persist despite mannitol and hypertonic saline, a bolus intravenous indomethacin may be considered
(0.5 mg/kg) [286]. L-ornithine L-arginine has not been shown
to be beneficial [287]. Mild hypothermia may be effective
for uncontrolled ICH [288,289], but other critical care literature reports that although hypothermia decreases ICP there
is no beneficial effect on mortality [290]. Hepatectomy is a
theoretical possibility as a bridging procedure to LTx for those
patients with devastating and medically uncontrolled ICH in
whom there is perceived to be no chance of spontaneous survival [291].
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Recommendations
Patients with low grade encephalopathy should be frequently evaluated for signs of worsening encephalopathy
(evidence level III, grade of recommendation 1).
In patients with grade 3 or 4 encephalopathy, intubation
should be undertaken to provide a safe environment and
prevention of aspiration. Regular evaluation for signs of
intracranial hypertension should be performed (evidence
level III, grade of recommendation 1).
Trans-cranial Doppler is a useful non-invasive monitoring
tool (evidence level II-3, grade of recommendation 1).
Invasive intracranial pressure monitoring should be considered in a highly selected subgroup of patients, who
have progressed to grade 3 or 4 coma, are intubated
and ventilated and deemed at high risk of ICH, based
on the presence of more than one of the following variables: a) young patients with hyperacute or acute presentations, b) ammonia level over 150–200 lmol/L that does
not drop with initial treatment interventions (RRT and
fluids), c) renal impairment and d) vasopressor support
(>0.1 lg/kg/min) (evidence level II-3, grade of recommendation 1).
Mannitol or hypertonic saline should be administered for
surges of ICP with consideration for short-term hyperventilation (monitor reverse jugular venous saturation to prevent excessive hyperventilation and risk of cerebral
hypoxia). Mild hypothermia and indomethacin may be
considered in uncontrolled ICH, the latter only in the
context of hyperaemic cerebral blood flow (evidence level
II-2, grade of recommendation 1).
Considerations for future studies
Accurate non-invasive assessment of ICP should be developed and validated.
Relationship
irritation.
between
inflammation
and
cerebral
Modulators of cerebral inflammation need to be studied.
Artificial and bioartificial liver devices
Liver assist devices have received much attention over recent
years in the hope that they can provide an effective ‘‘bridge” to
transplantation or recovery of liver function, mitigating the need
for transplantation. Unfortunately, the dream of a mechanical
‘‘proxy liver” is a long way from being realised.
Preliminary artificial liver support devices were essentially filters designed to remove toxins through haemodialysis or adsorption using charcoal, and failed to show a survival benefit in ALF
[292,293]. In the future, it will be essential to learn the lessons
of the past, i.e., that case series always seem to show benefit,
whilst well-designed clinical randomised controlled trials (RCTs)
often fail to fulfil the hopes of initial reports.
The Molecular Absorbent and Recirculating System (MARSÒ)
system utilises a hollow fibre, double-sided, albuminimpregnated dialysis membrane, designed to extract proteinbound toxins into the albumin dialysate [294]. Initial reports
suggested improvements in both systemic and cerebral
haemodynamic parameters and improvements in HE in patients
with ALF [295–297]. The PrometheusÒ system, which separates
plasma and treats it over adsorbent columns, has reported benefit
in AoCLF but has not been studied in ALF [298,299]. At least 12
RCTs of these devices have been performed and have been
systematically reviewed several times; overall, these devices
improve HE but have no mortality benefit in ALF, nor do they
show benefit in AoCLF [300,301].
The most recent trial from France examines ALF treated with
the current care standard or MARS. Overall there was no mortality benefit, although a trend for improved survival was seen in
non-transplanted patients with paracetamol induced hepatotoxicity [302]. Two factors should be considered in assessing the
outcome from this study. Firstly, that although paracetamol
induced hepatotoxicity is an aetiology with gross physiological
disarray, these patients have the best chance of spontaneous
survival. Secondly, that the median time to LTx in this study
was 16 h, with a median of 1 MARS treatment prior to LTx.
Therefore, it would be unrealistic to expect any system to have
an impact on mortality over such a short period. Subgroup analysis suggested a trend to better outcome in those who received
three treatments.
The biological systems of artificial liver support are more
complex, but allow the opportunity to facilitate both clearance
and metabolism of toxins, and support of hepatocyte function.
These may be divided into whole organ perfusion (human or
xenoperfusion), hepatocytes (porcine or hepatoblastoma) presented on columns and perfused following plasma separation,
and transplantation of either hepatocytes or stem cells.
In case series, the original system of porcine hepatocytes
and charcoal adsorbents (BAL) showed benefit in measured
physiological parameters, biochemical variables and ICP
[303,304]. Unfortunately, the subsequent RCT, including
patients with primary graft non-function, failed to show
improvement in terms of mortality or neurological outcome
and complications [304]. There has been an increasing concern
raised in utilising xenoperfusion techniques, due to the potential risk of viral transmission. Artificial bioreactors have therefore
moved
towards
incorporating
hepatocyte
and
hepatoblastoma cell lines. Biomedical engineering of these systems has developed vastly over the last 20 years and continues
to rapidly evolve.
The Extracorporeal Liver Assist Device (ELADÒ) system,
which utilises hepatoblastoma cell lines, has been studied in
various contexts and shows some benefit in physiology and biochemical parameters [305]. However, it has failed to show a
mortality benefit in ALF. This system provides a greatly
increased hepatocyte mass, and a RCT in AoCLF and ALF patients
is in progress.
The opportunity for hepatocyte or stem cell transplantation
remains an exciting proposition. Case series in children suggests
a benefit, especially to metabolic disease states. Further studies
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Clinical Practice Guidelines
are needed to examine the opportunities in adults with ALF,
although the potential could be limited by the volume of cells
required. Clarification as to the most appropriate site and mode
of cell delivery will also require investigation [306,307].
Plasma exchange (PE) in patients with ALF, undertaken on the
first 3 days of admission to critical care, has been shown to have
physiological and biochemical benefits, and to decrease ICP in
case series [308,309]. A recently published RCT in which PE was
undertaken, replacing plasma with fresh frozen plasma on a 1:1
ratio, demonstrated a mortality benefit in patients with ALF
who did not undergo transplantation. The survival benefit was
also seen in those who fulfilled poor prognostic criteria but
who were not listed due to co-morbidity. Furthermore, PE
appears to modify monocyte immune function, offering putative
rationale for survival benefit, in addition to the immediate clearance of mediators and replacement of plasma derived factors
[310].
Despite all these liver assist systems, the emphasis must
remain on provision of high general standards of critical care.
Physiological derangement in ALF can often be appropriately
managed with the organ support techniques described previously, including consideration for the use of beta blockers, as suggested by a recent study [311]. Biochemistry can also be
improved by appropriate fluid resuscitation and RRT, both of
which have been shown to decrease bilirubin and ammonia
[312].
All the devices described above are likely to affect clearance of
antimicrobial drugs and sedatives. Therefore, consideration must
be given to appropriate dosing schedules [313,314]. Anticoagulation of artificial circuits is variable and, as with RRT, a variety of
solutions may be considered. These should recognise that
patients with ALF will be resistant to heparin effects related to
low anti-thrombin III levels, and may have issues with citrate
[212,315,316].
One of the challenges in assessing the efficacy of liver assist
devices is that many of the prognostic markers of liver function,
which are used to assess clinical course, may be modulated by
the liver systems being studied. This is particularly the case
for such systems as PE, affecting coagulation, ammonia and
bilirubin; adsorbent systems affect bilirubin and ammonia, biological systems and potentially coagulation. The clinical skill will
be to recognise and separate liver recovery and regeneration
from the effect of any liver support system, and to make the
subsequent decisions as to whether LTx or other medical treatment is needed.
Recommendations
Liver support systems (biological or adsorbent) should
only be used in the context of RCT (evidence level II-1,
grade of recommendation 1).
Plasma exchange in RCT, has been shown to improve
transplant-free survival in patients with ALF, and to modulate immune dysfunction (evidence level I, grade of recommendation 1).
Plasma exchange may be of greater benefit in patients who
are treated early and who will not ultimately undergo LTx
(evidence level I, grade of recommendation 2).
1068
Considerations for future studies
Well-designed RCT of new liver support systems in welldefined patient cohorts.
Development of dynamic measures of liver function to
assess metabolic and synthetic capacity.
Antimicrobial clearance and dosing when utilising various
liver support systems such as PE.
Liver transplantation
The use of LTx has been the most significant development in the
treatment of ALF in 40 years and has transformed survival [8,15].
One year survival following emergency LTx is slightly worse than
for routine transplants, but stands at an impressive 80%. The
selection for LTx not only depends upon accurate prediction of
survival without transplant, but also requires consideration of
the survival potential after LTx, and whether a patient is too sick
to transplant [317].
Assessment and prognosis
Early recognition of patients who will not survive with medical
therapy alone is of great practical importance to identify potential candidates for LTx. As progression of MOF results in many
patients deteriorating whilst awaiting a transplant, identification
of candidates for transplantation should be achieved as quickly as
possible.
Prognostic assessment should take place both in the transplant centre and the site of first presentation, as decisions related
to patient transfer and LTx must be made at the earliest opportunity. A low threshold must be maintained for discussion in relation to management.
Clinical features indicative of poor prognosis
Even at an early stage of disease, there may be apparent clinical
features that are highly suggestive of an expected poor survival
with medical management alone, and may be used for risk
stratification.
Encephalopathy. The presence of an altered level of consciousness resulting from HE is of great prognostic importance. The
central positioning of HE in definitions of adult ALF reflects
this, with development indicating critically impaired liver
function. In patients with subacute presentations, even low
grade HE may indicate extremely poor prognosis, whereas
survival with medical management may be good in hyperacute disease and HE of equivalent severity. Adoption of a
single threshold of HE severity to mark transition from liver
‘‘injury” to ‘‘failure” across all presentations and etiologic
groups is thus overly simplistic; the lack of agreed definitions
complicates the literature. However, as a rule, any evidence
of HE should prompt local critical care assessment, discussion
and transfer to a specialist liver centre. When multiple
possible causes of reduced consciousness exist, a significantly
elevated arterial ammonia concentration is a reliable indicator
of HE.
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Extrahepatic organ failure. Non-liver organ failure, particularly
renal, is a marker of illness severity and associated with increased
mortality [44,209,267]. It indicates need for critical care review
and intervention and should trigger discussion with a specialist
centre in relation to management and possible transfer.
Adverse aetiology and presentation. Even now, subacute presentation of ALF and cases of indeterminate aetiology have consistently poor survival without LTx, and represent triggers for
immediate discussion with a specialist centre [9,93].
Severity of liver injury. In patients without HE, progression of disease is more likely in conjunction with major liver dysfunction. In
those with established ALF, poor prognostic criteria are more
likely to be fulfilled with a need for transplantation in patients
with significant liver injury. Whilst laboratory parameters of
coagulation disturbance are of prognostic significance in all
causes of ALF, the thresholds triggering clinical concern vary by
aetiology, evolution of the condition and age of the patient. For
example, an INR of 2.5 would be of immediate concern in
subacute ALF but not in paracetamol related disease; a factor V
level <20% may indicate a poor prognosis in patients of 30 years
or younger, but a higher threshold of <30% is of equivalent
significance in older patients [318–320]. Another issue is the
lack of a consistent international measure of coagulation, with
considerable variation in the frequently reported INR measure.
Some consistency may be achieved with reporting of PT and
control values.
The significance of specific biochemical markers of liver injury
may also vary by aetiology. Bilirubin level, for example, is not of
prognostic value in patients with paracetamol related disease but
is a key predictor of outcome in many cases with nonparacetamol causes, especially in subacute and acute presentation [321,322].
Transplantation selection criteria
Worldwide, different prognostic evaluation systems to select
candidates for transplantation are in use. These utilise features
associated with poor prognosis derived from analyses of historic
patient cohorts managed with and without transplantation
[267,274,318,321,322]. Whilst details differ, they share common
features (Table 11A). The presence of HE is a key indicator, with
further consideration of patient age and liver injury severity
assessed by the magnitude of coagulopathy or jaundice. In general, falling transaminases, increasing bilirubin and INR and
shrinking liver are poor prognostic signs and should result in considering transfer of patient to a transplant centre.
Although in active and apparently successful clinical use, published data on the performance of the selection criteria are scant,
and no system has been universally adopted. The two most commonly used systems in Europe are the Kings College and the Clichy criteria (Table 11B). Of these, the performance of the Kings
College criteria are best characterised; meta-analyses confirm
clinically acceptable specificity, but more limited sensitivity
[263,324,325]. A recent report of the performance of the Clichy
criteria suggested a reduced sensitivity and specificity, which
could be improved by separating paracetamol and nonparacetamol cases as well as including bilirubin and creatinine
clearance in the model [20]. Furthermore, the UK has recently
modified the national transplant listing criteria, increasing the
threshold for concentrations of lactate in paracetamol induced
ALF and allowing listing of subacute cases with predicted poor
prognosis without HE [317].
With improvements in medical supportive care in some
aetiologies of ALF, particularly paracetamol induced disease and
other hyperacute aetiologies, a greater proportion of patients will
now survive spontaneously. Thus, prognostic systems calibrated
from patients treated decades ago may no longer be appropriate.
Studies report evidence of increasingly poor performance over
time [263,325]. To address these limitations, a wide variety of
alternate prognostic systems and markers to replace or
supplement existing criteria have been proposed (Table 12).
These include the use of routine laboratory measures, including
specific measures such as blood lactate or phosphate, or
composite laboratory measures such as the MELD score
[203,230,246,322]. Novel replacement criteria include those
based upon routine laboratory measures and clinical findings,
and those utilising novel markers of immune activation or liver
cell injury [240,246,248,267]. Additional proposed indicators of
liver dysfunction include those which dynamically assess hepatic
metabolism of marker substances, including indocyanine green,
galactose or methacetin [326–331]. Many new marker studies
report better diagnostic performance than existing criteria but
are often small in size, have limited methodological quality and
are seldom internally or externally validated. Consequently,
few (if any) have been adopted internationally and cannot be
recommended for routine use.
Recommendations
Prognostic assessment should take place not only in the
transplant centre but also at the site of first presentation,
as decisions in relation to patient transfer to a specialist
centre must be made at the earliest opportunity (evidence
level III, grade of recommendation 1).
Development of encephalopathy is of key prognostic
importance, with onset indicating critically impaired liver
function. In subacute presentations, even low grade
encephalopathy may indicate extremely poor prognosis
(evidence level II-2, grade of recommendation 1).
Prognosis is worse in patients with more severe liver
injury, extrahepatic organ failure and subacute presentations (evidence level II-3, grade of recommendation 1).
Transplantation should be considered in those patients
fulfilling Clichy or Kings College criteria (evidence level
II-2, grade of recommendation 1).
Considerations for future studies
Future studies should prospectively assess the current natural history of the condition, be of high methodological
quality and sufficient size, enrolling from multiple centres.
Future studies should avoid the assumption that transplantation equals non-survival for prognostic modelling
purposes.
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Clinical Practice Guidelines
Table 11. (A) Acute Liver Failure Poor Prognosis Criteria in use for selection of candidates for Liver Transplantation. (B) Criteria for emergency liver transplantation.
A
Factor
Clichy [323]
Kings College [321]
Japanese [6]
Agey
Aetiology
Encephalopathyy
Bilrubin*
Coagulopathyy
+
+
+
+
+
+
±
+
+
+
+
+
B
King’s College criteria
ALF due to paracetamol
Arterial pH <7.3 after resuscitation and >24 h since ingestion
Lactate >3 mmol/L or
The 3 following criteria:
o Hepatic encephalopathy >grade 3
o Serum creatinine >300 lmol/L
o INR >6.5
ALF not due to paracetamol
INR >6.5 or
3 out of 5 following criteria:
o Aetiology: indeterminate aetiology hepatitis, drug-induced hepatitis
o Age <10 years or >40 years
o Interval jaundice-encephalopathy >7 days
o Bilirubin >300 lmol/L
o INR >3.5
Beaujon-Paul Brousse criteria (Clichy)
y
*
Confusion or coma (hepatic encephalopathy stage 3 or 4)
Factor V <20% of normal if age <30 year
or
Factor V <30% if age >30 year
Factors common to all prognostic models.
Bilirubin not included in paracetamol criteria.
Liver transplantation: Ethical issues, initial postoperative period and
outcome
Who to transplant: Ethical issues
One of the key issues for ALF is to determine those patients who
will die, and those who will spontaneously survive without LTx.
Thus, criteria for the indications of emergency LTx are mandatory. In addition, these criteria are needed early in the disease
course, in order to have time to find a suitable donor should
LTx be required.
Psychological assessment of the patient is frequently difficult
in the time frame available, due to the emergency context and the
presence of HE. In this context, the decision to transplant or not is
based on specific issues such as expected compliance, familial
status or environment. In addition, some causes of ALF commonly
affect patients considered at risk for non-compliance with medication and hospital attendance. As an example, acute hepatitis B
can be the consequence of intravenous drug use. Some patients
may have a history suggestive of other substance dependency,
albeit not responsible for the liver failure. During decision making, several factors should be taken into account: the age of the
patient, past history of suicide attempts, and absence of compli-
1070
ance with any previous medical treatments. It is essential to
obtain information from the family and friends of the patient,
family doctors, psychiatrists and to solicit input from all members of the multidisciplinary team. In ALF, some classical contraindications to LTx in chronic liver disease might be set aside,
such as suicide attempt, current consumption of alcohol or
drug-addiction and chaotic psychosocial life. Thus, the decision
to transplant or not based on psychosocial factors, is complex
and requires clear documentation and rationale. However, the
long-term outcome is favourable with high levels of treatment
compliance [332]. There is likely considerable variation from centre to centre and country to country. In all cases, major efforts
should be undertaken to reconstitute the medical and psychosocial environment of the patient and ensure psychosocial support
whether the patient undergoes LTx or not. Contraindication to
transplantation may also be determined by: physical health
issues, age, cardiac and respiratory disease, recent malignancy,
pancreatitis and severe sepsis, unresponsive to treatment.
Timing and decisions
The prognosis of ALF has recently improved and several centres
have suggested that early referral is an important reason for this
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JOURNAL OF HEPATOLOGY
Table 12. Comparison of traditional criteria for emergency liver transplantation compared with new alternatives.
Prognostic variable
Aetiology
Predictor of poor prognostic outcome
Sensitivity
Specificity
KCC
Clichy criteria
All
All
Factor V; factor VIII/V ratio
Paracetamol
Phosphate
APACHE II
Gc-globulin
Paracetamol
All
All
69
86
91
91
89
68
73
30
92
76
91
100
100
87
68
100
Lactate
Paracetamol
81
95
a-Fetoprotein
MELD
Paracetamol
Paracetamol
Non-paracetamol
See Table 5
HE + Factor V <20% (age <30 yr) or <30% (age >30 yr)
Grade III-IV HE + Factor V <20%
Factor VIII/V ratio >30;
Factor V <10%
PO3
4 >1.2 mmol/L on day 2 or 3 post overdose
APACHE II >19
Gc-globulin <100 mg/L
Paracetamol
Non-paracetamol
Admission arterial lactate >3.5 mmol/L or >3.0 mmol/L
after fluid resuscitation
AFP <3.9 lg/L 24 h post peak ALT
MELD >33 at onset of HE
MELD >32
100
60
76
74
69
67
KCC, King’s College Hospital; APACHE, Acute Physiology and Chronic Health Evaluation; MELD, Model for end-stage liver disease.
observation. Indeed, this gives time to prevent progression of ALF
and to stabilise the patient prior to transplantation, in those who
fulfil poor prognostic features. In most European countries,
patients with criteria for LTx are on a transplant waiting list,
which gives the patient an absolute priority over other cases.
As and when a liver graft becomes available, the patient should
be re-assessed for their suitability to proceed regarding physiological status or improvement to the point where LTx is no longer
considered appropriate. In the context of living related donation,
LTx should not be undertaken without progression to poor prognostic criteria, in the same manner as cadaveric grafting [333].
When a patient is too sick for liver transplantation
The only definitive criteria contraindicating LTx is irretrievable
brain injury. This is normally defined as the persistent presence
of bilateral non-reactive pupils with no spontaneous ventilation,
loss of middle cerebral artery flow or loss of grey white matter
differentiation and evidence of uncal herniation. Bacteraemia,
present in 20–30% of patients, is not a contraindication to transplantation providing there is appropriate response to treatment.
Progressive vasoplegic shock with rapidly rising vasopressor
requirement and peripheral vascular failure would be considered
a relative contraindication to proceeding, as would severe haemorrhagic pancreatitis and extensive small bowel ischaemia.
Uncontrolled ARDS and haemorrhagic pancreatitis are also relative contraindications, as would be the finding of a markedly
low cardiac output state. Relative change, as opposed to absolute
values of prognostic variables, will inform the decision to proceed
to LTx. This decision should involve all members of the multidisciplinary team.
Type of graft
The main particularity of LTx for ALF is the context of emergency.
Therefore, the possibility of choosing the best graft is frequently
reduced, due to shortage of time. The classical procedure when
performing LTx is orthotopic LTx using a liver graft from a cadaveric donor. This approach is possible due to the high priority of
such patients on the waiting list in most countries. In many countries, it is therefore possible to transplant the ALF patient within
72 h of adding the patient to the waiting list. However, due to
the urgency, it is frequently necessary to use marginal donors:
aged donors or steatotic grafts. It has been shown that the use
of these high-risk grafts might have a deleterious impact on
post-transplant outcome and survival [16]. Due to the emergency
context, the use of ABO incompatible grafts has been advocated.
The successful use of ABO incompatible graft is possible but at a
much higher risk of severe rejection, infectious complications
and of mortality or retransplantation [334,335]. Other factors
associated with poorer outcome are age (>45 years) and vasopressor use. However, outcome has also improved over time
[16,336,337].
An interesting approach based on the potential regeneration
of the liver is auxiliary orthotopic liver graft (APOLT). The principle is to leave part of the native liver by performing a partial
hepatectomy and transplanting a partial liver graft from a
cadaveric donor in an orthotopic position [338]. Thus, the graft
is supposed to act as a bridge in helping the patient to survive
the period of ALF, until potential regeneration of the native liver.
If the liver function of the native liver returns to normal, then it
is possible to slowly and progressively reduce the immunosuppression, leading to progressive graft atrophy [339,340]. This
strategy is potentially more challenging, with an increased risk
of bleeding and more frequent post-transplant complications.
The overall survival is lower than for orthotopic LTx. Regeneration of the native liver does occur in a significant proportion of
cases, but can take prolonged periods of time to complete [341].
Therefore, the indications of APOLT are limited to patients with
a high potential of liver regeneration, young patients, patients
with ALF due to hepatitis A or paracetamol poisoning. It is not
appropriate in patients with severe grade HE and high risk of
brain death.
Living donor LTx is rarely used in Europe and USA due to the
rapid availability of cadaveric liver grafts. In addition, it can place
high emotional pressure on the donor’s family; the process of
organising the procedure in an emergency can increase the surgical risk for the donor. This is different in Asian countries, where
the availability of cadaveric liver donors is low and where living
donor LTx is undertaken on a routine basis. The results of living
donor LTx in patients with ALF in Asia are good, and similar to
cadaveric liver donor in Europe and USA [342].
Journal of Hepatology 2017 vol. 66 j 1047–1081
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Clinical Practice Guidelines
Specific issues and immediate complications
The context of LTx for patients with ALF is different to the elective situation; patients frequently have established extrahepatic
organ failure at the time of surgery, and marginal grafts are used
more frequently. The main cause of morbidity and mortality following LTx is that of sepsis, progressive organ failure in the context of vasoplegic shock, and liver graft dysfunction or failure.
Cerebral deaths resultant upon cerebral oedema and herniation
are now rare [8,317]. Retransplantation is more frequent than
in elective series. The main causes of retransplantation are primary graft non-function and severe dysfunction, and hepatic
artery thrombosis. However, outcome has also improved over
time.
Considerations for future studies
Definition and validation of contraindications to transplant in patients with ALF.
Definition and validation of futility of LTx in patients with
ALF.
Clarification of the role of auxiliary LTx in patients with
ALF.
Definition of long-term outcomes including quality of life
in both transplant recipients and spontaneous survivors.
Biomarkers of regenerative capacity.
HBV recurrence after LTx for fulminant hepatitis B or hepatitis delta
HBV recurrence can occur after transplantation for fulminant
hepatitis B but is much less frequent compared to patients transplanted for chronic liver disease due to HBV. With modern antiviral agents, it should no longer occur [343].
Quality of life and long-term survival
The quality of life of LTx survivors is generally good and seems
similar to that of patients transplanted for chronic liver disease.
The majority of young patients will return to a normal social
life and to work. Psychological troubles can be observed in
the early postoperative period and are explained mainly by
pre-transplant HE and by the fact that these patients were
not prepared psychologically for transplantation [332]. Longterm survival is generally good; there are few deaths one year
post-LTx. This is due in part to the young age of the patients,
the low rate of HBV recurrence in fulminant hepatitis B and
the absence of recurrence of hepatic diseases, although chronic
rejection remains a risk.
Recommendations
Assessment of patients with ALF for emergency LTx
requires input from a multidisciplinary team with appropriate experience in this process (evidence level III, grade
of recommendation 1).
Patients with ALF, potential for deterioration and who may
be candidates for LTx, should be transferred to specialist
units before the onset of HE to facilitate assessment (evidence level III, grade of recommendation 1).
Patients with ALF listed for LTx should be afforded the
highest priority for donated organs (evidence level III,
grade of recommendation 1).
Irreversible brain injury is a contraindication to proceeding with LTx (evidence level II-3, grade of recommendation 1).
Patients transplanted for acute HBV infection need ongoing therapy for suppression of viral replication (evidence
level II-3, grade of recommendation 1).
1072
Paediatric acute liver failure
ALF in children is defined as a multisystem syndrome with the
following components to the definition: hepatic-based coagulopathy defined as a PT >15 s or INR >1.5 not corrected by vitamin
K in the presence of clinical HE, or a PT 20 s or INR 2.0 regardless
of the presence or absence of HE. An essential component of the
definition is the absence of a recognised underlying chronic liver
disease. A difference of note is that HE is not considered to be an
essential component of the definition of ALF in children [96].
Common aetiologies
Acute viral hepatitis is the most common identified cause in most
of the series from Asia and South America. In contrast, in Europe
and North America, aetiology remains indeterminate in about
half of the patients. Patients in the indeterminate group tend to
have severe disease and a high fatality rate without LTx. About
10% of these patients can develop bone marrow failure either
simultaneously or a few weeks to months after the onset of
symptoms of ALF [344].
Paracetamol, the most common drug associated with ALF, is
safe when used in therapeutic doses in healthy children. However, inadvertent administration of higher doses of paracetamol
can lead to ALF. A detailed history of exposure to paracetamol
is helpful.
Autoimmune hepatitis, presenting as ALF can be difficult to
diagnose because some cases may not have antibody positivity
at presentation. Most of these patients have a liver-kidney microsomal antibody. Children with autoimmune hepatitis presenting
with ALF along with HE usually do not respond to any form of
immunosuppression and need urgent LTx [345,346]. Giant cell
hepatitis may also often present with autoimmune haemolytic
anaemia [347]. Unknown aetiology was frequently seen in a single centre study by Kathemann et al., with better prognosis seen
in older children [348].
Gestational alloimmune liver disease, earlier known as neonatal hemochromatosis (NH), is the most common cause of ALF in
the neonatal period [349]. Elevation of ferritin as a diagnostic test
is sensitive but not specific. Hypersaturation of transferrin with
Journal of Hepatology 2017 vol. 66 j 1047–1081
JOURNAL OF HEPATOLOGY
relative hypotransferrinaemia may be a valuable finding. A punch
biopsy specimen of buccal minor salivary glands is a useful diagnostic tool. Documentation of iron in these minor salivary glands
is highly suggestive of NH.
ALF due to underlying metabolic disease is an important differential in children. A high index of suspicion is important
because urgent intervention such as dietary manipulation or
disease-specific treatment may be lifesaving. ALF presentation
without jaundice should be an indicator to investigate underlying
metabolic conditions.
Mitochondrial hepatopathies should be considered if there is
evidence of hypoglycaemia, vomiting, coagulopathy, acidosis
and increased lactate with or without neurological symptoms.
Sodium valproate is known to unmask underlying mitochondrial
cytopathies [350]; hence, detailed investigations to exclude mitochondrial hepatopathies should be undertaken before injury is
ascribed to sodium valproate.
HLH is a common cause of ALF in children [39]. This condition
presents as a spectrum of inherited and acquired conditions, with
disturbed immunoregulation and coagulopathy, high fever, hepatosplenomegaly, high alkaline phosphatase, high lactate dehydrogenase, and abnormalities on peripheral blood film. Bone
marrow examination or liver biopsy is diagnostic.
LTx is the only proven treatment that has improved the outcome of ALF in children who fulfil poor prognostic criteria.
Criteria for listing are not validated but an INR >4 and total
bilirubin >300 lmol/L (17.6 mg/dl) irrespective of HE is the currently accepted criteria for listing in children because of poor
survival with medical management [351,352]. Contraindications
to LTx are fixed and dilated pupils, uncontrolled sepsis, and
severe respiratory failure (ARDS). Relative contraindications
are: accelerating inotropic requirements, infection unresponsive
to treatment, history of progressive or severe neurological
problems in which the ultimate neurological outcome may not
be acceptable, or systemic disorders such as HLH, where LTx is
not curative.
Recommendations
The definition of ALF in paediatrics is not dependent upon
the presence of encephalopathy (evidence level II-3,
grade of recommendation 1).
Some aetiologies are specific to paediatric patients – notably metabolic disorders (evidence level II-3, grade of
recommendation 1).
Transplantation criteria are different to those in adults
(evidence level II-3, grade of recommendation 1).
Prognosis
The prognosis of ALF varies greatly with the underlying aetiology.
PT or INR is the best indicator of survival. Fulminant Wilson disease is invariably fatal, and emergency LTx is the only effective
treatment. The revised Wilson disease prognostic index has been
useful in identifying the patients who have a high risk of mortality without LTx [61,97]. This index incorporates bilirubin, INR,
AST, white blood cell count, and albumin at presentation. A score
of 11 or more indicates high mortality, with 93% sensitivity and
98% specificity with a positive predictive value of 88%.
Considerations for future studies
International epidemiological studies in children with ALF.
Refining transplant criteria for paediatric cases.
Randomised or alternative methodologies to assess best
clinical practice for ALF management in children.
Management
A careful and detailed history should include the mode of onset of
illness, family history of liver disease, consanguinity, and exposure to drugs and toxins. Clinical examination could give diagnostic clues such as the presence of any herpetic vesicles, signs of
underlying chronic liver disease, and the presence of KayserFleischer rings on slit lamp examination.
Specific management pertaining to paediatric disease processes can be delineated as follows:
1) Protein restriction under 1 g/kg body weight is not recommended unless the patient has an underlying urea cycle
defect or organic acidaemia.
2) In neonatal liver failure, high dose intravenous acyclovir
should be commenced until herpes simplex virus infection
is excluded.
3) Prophylactic broad spectrum antibiotics and antifungals
should be used in children admitted to high dependency
or intensive care unit.
4) Use of ICP monitoring is not routinely indicated but may be
considered in children older than 2 years who have clinical
signs of increased ICP and are awaiting LTx.
5) Ventilatory support in the form of mechanical ventilation
is instituted when grade 3 HE develops or when patients
in grade 1 or 2 HE require sedation [96,351].
Conflict of interest
Dr. Bernardi, Dr. Simpson, Dr. Larsen, Dr. Wendon, Dr. Manns, and
Dr. Dhawan have nothing to disclose.
Yaron Ilan is a consultant for Immuron, Teva, Enzo Biochem,
Protalix, Therapix, Nasvax, Exalenz, Tiziana, and Natural Shield.
Dr. Escorsell report other from Vital Therapies, outside the
submitted work.
Dr. Bernal reports personal fees from Ocera Therapeutics, personal fees from Vital Therapies, outside the submitted work.
Dr. Samuel reports other from Astellas, other from BMS, other
from Gilead, other from LFB, other from MSD, other from Novartis, other from Roche, other from Biotest, other from Abbvie,
other from Intercept, outside the submitted work.
Acknowledgements
EASL would like to thank the reviewers for contributing their
expertise to the production of these recommendations: Ali Canbay, François Durand and Ludwig Kramer.
Journal of Hepatology 2017 vol. 66 j 1047–1081
1073
Clinical Practice Guidelines
The panel would like to also acknowledge the phenomenal
contribution of William Bernal, who has contributed to this work
and to the management of acute liver failure.
[21]
[22]
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jhep.2016.12.
003.
[23]
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